Heterocyclic compounds for treatment of huntington's disease

Abstract

The present disclosure provides a compound # imgabs0 # of formula (I) or a pharmaceutically acceptable salt thereof and the use of the compounds in, for example, treating a condition, disease or condition that is therapeutically beneficial to lowering mutant Huntingtin ("mHTT") in a subject, particularly in the treatment of Huntington's disease ("HD"). The disclosure also features compositions containing the above compounds as well as methods of using and making the compounds.

Description

[0001] Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 344,494, filed on May 20, 2022, under 35 U.S.C. §119(e), the entire contents of which are incorporated herein by reference. Background Art

[0003] Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder that affects three to seven people in every 100,000 worldwide. HD is caused by an expansion of the cytosine-adenine-guanine (CAG) repeat sequence in the huntingtin (HTT) gene, resulting in the production of a ubiquitously expressed pathogenic mutant HTT (mHTT) protein. The mutant huntingtin protein contains an abnormally long polyglutamine (polyQ) sequence corresponding to the CAG gene expansion; this protein exhibits toxic properties, causing neuronal dysfunction and death. Huntington's disease is characterized by reduced motor, cognitive, psychiatric, and functional abilities.

[0004] Several studies have made progress in identifying therapeutics to reduce HTT protein using a variety of tools, including ribonucleic acid (RNA) interference using short interfering RNA, short hairpin RNA or microRNA and antisense oligonucleotides ("ASO"), causing translation inhibition or messenger RNA (mRNA) degradation. However, these therapies require surgical delivery of viral vectors to reduce chronic HTT transcripts through RNAi, or require repeated infusion of ASOs into the cerebrospinal fluid ("CSF") via lumbar puncture in the clinic.

[0005] Recently, a platform of small molecule compounds that regulate RNA expression (i.e., splicing correction) is being developed. NVS-SM1 (LMI070), now known as branaplam, is a pyridazine derivative. Branaplam has been reported to reduce mHTT protein levels in cells from HD patients, HD mouse models, and blood samples from type I SMA patients treated orally for spinal muscular atrophy (NCT02268552). See Keller, C. et al., An Orally Available, Brain Penetrant, Small Molecule Lowers Huntingtin Levels by Enhancing Pseudoexon Inclusion, Nature Communications, (2022) 13:1150.

[0006] However, there are currently no approved disease-modifying treatments for HD, and thus there remains an unmet need for drugs that can be used to treat or improve HD. Thus, there is a need to find disease-modifying therapies (i.e., treatment options that can slow the progression of the disease) for HD. Summary of the invention

[0007] Described herein are compounds or pharmaceutically acceptable salts thereof that are useful for treating HD in a subject.

[0008] In one aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Where X 1 , X 2 , X 3 , X 4 , R 5 , R 6 and R 7 As defined herein.

[0011] Also provided is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0012] The present disclosure also provides a method of reducing mHTT in a subject, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0013] The present disclosure also provides a method of treating a disease or condition in a subject that is regulated at least in part by mHTT, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0014] The present disclosure further provides a method of inhibiting Huntington's disease ("HD") in a subject in need thereof, the method comprising administering to the subject an effective amount of (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0015] In certain embodiments of the disclosed methods, HD can be treated by reducing mHTT levels in a subject.

[0016] The present disclosure also provides the use of a compound of formula (I), a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same in any of the methods described herein. In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in any of the methods described herein is provided. In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for use in any of the methods described herein is provided. DETAILED DESCRIPTION

[0017] 1. Compounds

[0018] In a first aspect, the present disclosure provides a compound of formula (I):

[0019]

[0020] or a pharmaceutically acceptable salt thereof, wherein:

[0021] is a single bond or a double bond, provided that it contains X 1 , X 2 , X 3 and X 4 The ring is a bicyclic heteroaryl ring containing at least one N atom;

[0022] X 1 is C or N;

[0023] X 2 O, N or CR 2 ;

[0024] X 3 is N or C;

[0025] X 4 N, O, NR 4 or CR 4 ; The condition is that when X 1 When it is C, X 2 , X 3 and X 4 At least two of them are O, N or NR 4 ;

[0026] R 2 and R 4 When present, each is independently selected from H, halo and C 1-6 A group consisting of alkyl groups;

[0027] R 5 H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C1-6 Haloalkoxy;

[0028] R 6 is A, -N(R 6a )-A, -C(=O)A, -N(R 6a )C(=O)-A or -C(=O)N(R 6a )-A, and R 7 is B; in addition, when X 1 When N is 6 is B and R 7 is A;

[0029] R 6a Is H or C 1-3 alkyl;

[0030] A is -C 1-6 Alkylene-NR 9 R 10 , 4 to 10 membered carbocyclic group, -C 1-6 Alkylene-(4- to 10-membered carbocyclyl), Het or –C 1-6 Alkylene-Het; wherein:

[0031] R 9 Is H or C 1-6 alkyl;

[0032] R 10 It is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, –C 1-6 Alkylene-C 3-6 Cycloalkyl or –C 1-6 Alkylene-Het 1 , where Het 1 is a 4-6 membered saturated heterocyclic group;

[0033] Het is a 4- to 12-membered saturated heterocyclic group, which is optionally substituted by -NR 9 R 10 or –C 1-6 Alkylene-NR 9 R 10 and optionally further substituted by 1 to 4 R 11 replace;

[0034] The 4- to 10-membered carbocyclic group represented by A is optionally substituted by -NR 9 R 10 or –C 1-6 Alkylene-NR 9 R 10 and optionally substituted by 1 to 2 R 11 Replace; where:

[0035] R 11 is independently selected at each occurrence from halo, -C(=O)R 12 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl, –C 1-6 Alkylene-C 3-6 Cycloalkyl, Het 2 and –C 1-6 Alkylene-Het 2 , where Het 2 is a 4- to 6-membered saturated heterocyclic group or a 5- to 10-membered heteroaryl group, wherein said Het 2 or C 3-6 Cycloalkyl is optionally substituted by one or more independently selected from halo, C 1-6 Alkoxy and C 1-6 The alkyl group is substituted with a substituent; wherein R 12 It is H, D, halogenated, C 1-3 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl;

[0036] B is a 6- to 10-membered aryl, a 4- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl, the 4- to 10-membered heterocyclyl and the 5- to 10-membered heteroaryl represented by B are optionally replaced by one or more R 8 Replace;

[0037] R 8 It is halogenated, -CN, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-membered or 6-membered heteroaryl, C 1-6 Haloalkyl or C 1-6 Alkoxy, or two R 8 Together with the intervening atoms, it forms a 8b substituted 4 to 7 membered heterocyclic group; wherein R 8 The 5-membered or 6-membered heteroaryl represented by 8a Substitution; wherein R 8a It is C 1-3 alkyl; and R 8b It is C 1-3 alkyl or oxo; and

[0038] wherein the heterocyclyl contains 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur; and the heteroaryl contains 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0039] In a first embodiment, the present disclosure provides a compound of formula (I):

[0040]

[0041] or a pharmaceutically acceptable salt thereof, wherein:

[0042] is a single bond or a double bond, provided that it contains X 1 , X 2 , X 3 and X 4 The ring is a bicyclic heteroaryl ring containing at least one N atom;

[0043] X 1 is C or N;

[0044] X 2 O, N or CR 2 ;

[0045] X 3 is N or C;

[0046] X 4 Yes N, NR 4 or CR 4 ; The condition is that when X 1 When it is C, X 2 , X 3 and X 4 At least two of them are O, N or NR 4 ;

[0047] R 2 and R 4 When present, each is independently selected from H, halo and C 1-6 A group consisting of alkyl groups;

[0048] R 5 It is halogenated;

[0049] R 6 is A, -N(R 6a )C(=O)-A or -C(=O)N(R 6a )-A, and R 7 is B; or

[0050] When X 1 When N is 6 is B and R 7 is A;

[0051] R 6a Is H or C 1-3 alkyl;

[0052] A is -C 1-6 Alkylene-NR9 R 10 , 4- to 10-membered saturated carbocyclic group, Het or -C 1-6 Alkylene-Het; wherein

[0053] R 9 Is H or C 1-6 alkyl;

[0054] R 10 It is H, C 1-6 Alkyl or -C 1-6 Alkylene-Het 1 , where Het 1 is a 4-6 membered saturated heterocyclic group;

[0055] Het is a 4- to 10-membered saturated heterocyclic group, provided that when the 4- to 10-membered saturated heterocyclic group represented by Het does not contain a ring N atom, the group is replaced by -NR 9 R 10 and optionally further substituted with 1 to 2 R 11 and when the 4- to 10-membered saturated heterocyclic group represented by Het contains one or more ring N atoms, the group is optionally substituted by 1 to 3 R 11 replace;

[0056] The 4- to 10-membered saturated carbocyclic group represented by A is -NR 9 R 10 and optionally substituted by 1 to 2 R 11 Replace;

[0057] R 11 is independently selected at each occurrence from halo, -C(=O)R 12 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 3-6 Cycloalkyl; wherein R 11 The C 3-6 Cycloalkyl is optionally substituted with one or more independently selected from halo and C 1-6 The alkyl group is substituted with a substituent; wherein R 12 It is H, C 1-3 Alkyl or C 3-6 Cycloalkyl;

[0058] B is a 6- to 10-membered aryl, a 4- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl, the 4- to 10-membered heterocyclyl and the 5- to 10-membered heteroaryl represented by B are optionally replaced by one or more R 8 Replace;

[0059] R8 It is halogenated, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, or two R 8 Together with the intervening atoms, it forms a 8b substituted 5- to 7-membered heterocyclic group; wherein R 8 The 5-membered or 6-membered heteroaryl represented by 8a Substitution; wherein R 8a It is C 1-3 alkyl; and R 8b It is C 1-3 alkyl or oxo; and

[0060] wherein the heterocyclyl contains 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur; and the heteroaryl contains 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0061] In a second embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX):

[0062]

[0063] Definitions of the variables are provided in the first aspect or first embodiment.

[0064] In an alternative second embodiment, the present disclosure provides a compound according to the first aspect or first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II), (III), (IV), (V), (VI), (VII) or (VIII):

[0065]

[0066] Definitions of the variables are provided in the first aspect or first embodiment.

[0067] In a third embodiment, the present disclosure provides a compound according to the first aspect or the first or second embodiment or a pharmaceutically acceptable salt thereof, wherein the compound is represented by formula (II):

[0068]

[0069] Definitions of the variables are provided in the first aspect or the first or second embodiment.

[0070] In a fourth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to third embodiments, or a pharmaceutically acceptable salt thereof, wherein R 5 is H, halogenated, C 1-3 Alkyl, C 1-3 Haloalkoxy or C 1-3 Alkoxy. The definitions for the remaining variables are provided in the first aspect or any one of the first through third embodiments, or any alternative embodiments described therein.

[0071] In an alternative fourth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to third embodiments, or a pharmaceutically acceptable salt thereof, wherein R 5 is F or Cl. The definitions of the remaining variables are provided in any one of the first aspect or first through third embodiments, or any alternative embodiments described therein.

[0072] In a fifth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to third embodiments, or a pharmaceutically acceptable salt thereof, wherein R 5 It is H, F, Cl, -CH 3 、-OCHF 2 、-OCH 3 or -OCF 3 The definitions of the remaining variables are provided in any of the first aspect or first through third embodiments, or any alternative embodiments described therein.

[0073] In an alternative fifth embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to third embodiments, or a pharmaceutically acceptable salt thereof, wherein R 5 is F. The definitions of the remaining variables are provided in the first aspect or any one of the first through third embodiments, or any alternative embodiments described therein.

[0074] In a sixth embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to fifth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is A, -N(R 6a )-A、-N(R 6a )C(=O)-A or -C(=O)N(R 6a )-A;R 7 is B and R 6a is H or –CH 3 The definitions of the remaining variables are provided in the first aspect or any one of the first through fifth embodiments, or any alternative embodiments described therein.

[0075] In an alternative sixth embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to fifth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 6 is A, -NHC(=O)-A or -C(=O)NH-A and R 7 is B. The definitions of the remaining variables are provided in the first aspect or any one of the first through fifth embodiments, or any alternative embodiments described therein.

[0076] In a seventh embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to fifth embodiments, or a pharmaceutically acceptable salt thereof, wherein when X 1 When N is 6 is B and R 7 is A. The definitions of the remaining variables are provided in the first aspect or any one of the first through fifth embodiments, or any alternative embodiments described therein.

[0077] In an eighth embodiment, the present disclosure provides a compound according to the seventh embodiment or a pharmaceutically acceptable salt thereof; wherein

[0078] X 1 is N;

[0079] X 2 Yes CR 2 ;

[0080] X 3 It is C;

[0081] X 4 is N;

[0082] R 6 is B; and

[0083] R 7 It is A.

[0084] Definitions of the remaining variables are provided in the seventh embodiment.

[0085] In a ninth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein when R 7 When it is B, R 6 is A. The definitions of the remaining variables are provided in the first aspect or any one of the first through sixth embodiments, or any alternative embodiments described therein.

[0086] In a tenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein when X 1 When N is 6 Yes-N(R6a )-A、-N(R 6a )C(=O)-A or -C(=O)N(R 6a )-A and R 7 is B; and where R 6a is H or –CH 3 The definitions of the remaining variables are provided in the first aspect or any one of the first through sixth embodiments, or any alternative embodiments described therein.

[0087] In an alternative tenth embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to sixth embodiments, or a pharmaceutically acceptable salt thereof, wherein when X 1 When N is 6 is -NHC(=O)-A or -C(=O)NH-A and R 7 is B. The definitions of the remaining variables are provided in the first aspect or any one of the first through sixth embodiments, or any alternative embodiments described therein.

[0088] In an eleventh embodiment, the present disclosure provides a compound according to the tenth embodiment, or a pharmaceutically acceptable salt thereof, wherein

[0089] X 1 is N;

[0090] X 2 Yes CR 2 ;

[0091] X 3 It is C;

[0092] X 4 is N;

[0093] R 6 Yes-N(R 6a )-A、-N(R 6a )C(=O)-A or -C(=O)N(R 6a )-A;

[0094] R 6a is H or –CH 3 ;and

[0095] R 7 It is B.

[0096] Definitions for the remaining variables are provided in the tenth embodiment or any alternative embodiment described therein.

[0097] In an alternative eleventh embodiment, the present disclosure provides a compound according to the tenth embodiment, or a pharmaceutically acceptable salt thereof, wherein

[0098] X1 is N;

[0099] X 2 Yes CR 2 ;

[0100] X 3 It is C;

[0101] X 4 is N;

[0102] R 6 is -NHC(=O)-A or -C(=O)NH-A; and

[0103] R 7 It is B.

[0104] Definitions for the remaining variables are provided in the tenth embodiment or any alternative embodiment described therein.

[0105] In a twelfth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to eleventh embodiments, or a pharmaceutically acceptable salt thereof, wherein:

[0106] A is for – C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-NR 9 R 10 or –C 1-6 Alkylene-Het; wherein

[0107] A represents -C 1-6 The Het in alkylene-Het is a 4- to 6-membered monocyclic saturated heterocyclic group containing a ring N atom; and

[0108] R 9 and R 10 Each independently is H or C 1-4 alkyl.

[0109] Definitions for the remaining variables are provided in the first aspect or any one of the first through eleventh embodiments, or any alternative embodiments described therein.

[0110] In the thirteenth embodiment, the present disclosure provides a compound according to the twelfth embodiment or a pharmaceutically acceptable salt thereof, wherein A represents -C 1-6 The Het in alkylene-Het is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl. The definitions of the remaining variables are provided in the twelfth embodiment.

[0111] In the fourteenth embodiment, the present disclosure provides a compound according to the twelfth embodiment or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

[0112]

[0113] Definitions of the remaining variables are provided in the twelfth embodiment.

[0114] In an alternative fourteenth embodiment, the present disclosure provides a compound according to the twelfth embodiment, or a pharmaceutically acceptable salt thereof, wherein

[0115] A is selected from the group consisting of:

[0116]

[0117] Definitions of the remaining variables are provided in the twelfth embodiment.

[0118] In a fifteenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to eleventh embodiments, or a pharmaceutically acceptable salt thereof, wherein:

[0119] A is a 5- to 6-membered monocyclic carbocyclyl, a 5- to 8-membered bicyclic saturated bridged carbocyclyl, or Het;

[0120] The Het represented by A is a 4- to 7-membered monocyclic saturated heterocyclic group, a 6- to 8-membered bicyclic saturated bridged heterocyclic group, or a 7- to 12-membered bicyclic saturated spiro or fused heterocyclic group; provided that when the Het represented by A does not contain a ring N atom, the Het is replaced by -NR 9 R 10 or –C 1-6 Alkylene-NR 9 R 10 and optionally further 1 to 2 R 11 and when the Het represented by A contains one or more ring N atoms, the Het is optionally substituted by 1 to 2 R 11 replace; and

[0121] The 5- to 8-membered bicyclic saturated bridged carbocyclic group represented by A is -NR 9 R 10 , a 4- to 6-membered monocyclic saturated heterocyclic group or -C 1-6 Alkylene-NR 9 R 10 and optionally further 1 to 2 R 11 replace; and

[0122] R 9 and R 10 Each independently is H or C 1-4 alkyl.

[0123] Definitions for the remaining variables are provided in the first aspect or any one of the first through eleventh embodiments, or any alternative embodiments described therein.

[0124] In an alternative fifteenth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to eleventh embodiments, or a pharmaceutically acceptable salt thereof, wherein:

[0125] A is a 5- to 6-membered monocyclic saturated carbocyclyl, a 5- to 8-membered bicyclic saturated bridged carbocyclyl or Het;

[0126] The Het represented by A is a 4- to 6-membered monocyclic saturated heterocyclic group, a 6- to 8-membered bicyclic saturated bridged heterocyclic group, or a 7- to 10-membered bicyclic saturated spiro or fused heterocyclic group; provided that when the Het represented by A does not contain a ring N atom, the Het is replaced by -NR 9 R 10 and optionally further 1 to 2 R 11 and when the Het represented by A contains one or more ring N atoms, the Het is optionally substituted by 1 to 2 R 11 replace; and

[0127] The 5- to 8-membered bicyclic saturated bridged carbocyclic group represented by A is -NR 9 R 10 and optionally further 1 to 2 R 11 replace;

[0128] R 9 and R 10 Each independently is H or C 1-4 alkyl.

[0129] Definitions for the remaining variables are provided in the first aspect or any one of the first through eleventh embodiments, or any alternative embodiments described therein.

[0130] In the sixteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 2-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.1.1]heptyl, 2-azabicyclo[3.1.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 1-azaspiro[3.3]heptyl, 2-azaspiro[4.5]decyl, 4-azaspiro[4.5]decyl, 1-azaspiro[2.5]octyl, 8-azaspiro[4.5]decyl, 8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.2.1]octyl, 9-diazaspiro[5.5]undecyl, 2-azabicyclo[4.1.0]heptyl, 3-azabicyclo[4.1.0]heptyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.3]hexyl, 4-azaspiro[2.4]heptyl, 6-azaspiro[3.4]octyl, 2-azaspiro[4.4 ]nonyl, 2-azaspiro[3.5]nonyl, 2-azaspiro[3.4]octyl, 1-oxa-9-azaspiro[5.5]undecyl, 3-azabicyclo[3.1.0]hexyl, diazaspiro[4.5]decane, 7-diazaspiro[3.5]nonyl, diazaspiro[4.5]decyl, 7-diazaspiro[4.4]nonyl, 1-azabicyclo[3.2.1]octyl, diazaspiro[5.5]undecyl, azepanyl, 7-azaspiro[3. 5]nonyl, 7-azaspiro[3.5]nonyl, 5-oxa-2-azaspiro[3.4]octyl, diazabicyclo[3.2.0]heptyl, 3-azabicyclo[3.2.0]heptyl, octahydro-cyclopenta[c]pyrrolyl, hexahydro-1H-pyrrolo[3,4-c]pyrrolyl, octahydro-indolizinyl, 8-diazabicyclo[4.2.0]octyl, octahydro-isoindolyl or 1,8-diazaspiro[4.5]decane, each of which is optionally substituted by one or two R 11 The definitions of the remaining variables are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0131] In an alternative sixteenth embodiment, the disclosure provides a compound according to the fifteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 2-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.1.1]heptyl, 2-azabicyclo[3.1.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 1-azaspiro[3.3]heptyl, 2-azaspiro[4.5]decyl, 4-azaspiro[2.5]octyl, 8-azaspiro[4.5]decyl, 8-azabicyclo[3.2.1]octyl or 7-azaspiro[3.5]nonyl, each of which is optionally substituted by one or two R 11The definitions of the remaining variables are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0132] In the seventeenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment or the sixteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

[0133]

[0134] Each of which is optionally replaced by one or two R 11 The definitions of the remaining variables are provided in the fifteenth or sixteenth embodiment, or any alternative embodiment described therein.

[0135] In an alternative seventeenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment or the sixteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

[0136]

[0137] Each of which is optionally replaced by one or two R 11 The definitions of the remaining variables are provided in the fifteenth or sixteenth embodiment, or any alternative embodiment described therein.

[0138] In the eighteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, tetrahydro-2H-pyranyl, 3-oxetanyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, -CH 2 -cyclobutyl, bicyclo[2.2.2]octyl, spiro[5.3]nonyl or 2-oxobicyclo[2.1.1]hexyl, each of which is replaced by -NR 9 R 10 and optionally further 1 to 2 R 11 The definitions of the remaining variables are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0139] In an alternative eighteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is cyclopentyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.2]octyl or 2-oxobicyclo[2.1.1]hexyl, each of which is replaced by -NR 9 R 10 and optionally further 1 to 2 R 11The definitions of the remaining variables are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0140] In the nineteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment or the eighteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

[0141]

[0142] Each of which is –NR 9 R 10 and optionally further 1 to 2 R 11 The definitions of the remaining variables are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0143] In an alternative nineteenth embodiment, the present disclosure provides a compound according to the fifteenth embodiment or the eighteenth embodiment, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

[0144]

[0145] Each of which is –NR 9 R 10 and optionally further 1 to 2 R 11 The definitions of the remaining variables are provided in the fifteenth embodiment or any alternative embodiment described therein.

[0146] In the twentieth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to nineteenth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 11 is independently selected at each occurrence from halo, -C(=O)R 12 , C 1-6 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, Het 2 and -C 1-6 Alkylene-Het 2 , where Het 2 is a 4-6 membered saturated heterocyclic group or a 5- to 6-membered heteroaryl group; wherein R 11 The C 3-6 Cycloalkyl or Het 2 Optionally, one to four independently selected from halo, C 1-4 Alkoxy and C 1-4 The alkyl group is substituted with a substituent; and R 12It is H, D, halogenated, C 1-4 Alkoxy, C 1-2 Alkyl, C 3-4 The definitions for the remaining variables are provided in the first aspect or any one of the first through nineteenth embodiments, or any alternative embodiments described therein.

[0147] In an alternative twentieth embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to nineteenth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 11 is independently selected at each occurrence from halo, -C(=O)R 12 , C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl; wherein R 11 The C 3-6 The cycloalkyl group is optionally substituted by one to three independently selected from F, Cl and C 1-4 The alkyl group is substituted with a substituent; and R 12 It is H, C 1-2 Alkyl, C 3-4 The definitions for the remaining variables are provided in the first aspect or any one of the first through nineteenth embodiments, or any alternative embodiments described therein.

[0148] In the twenty-first embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twentieth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 11 is independently selected at each occurrence from F, -C(=O)CH 3 、-C(=O)CH 2 CH 3 , -C(=O)cyclopropyl, -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-C(CH 3 ) 3 、-CH 2 C(CH 3 ) 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH3 、-CH 2 CHF 2 、-CH 2 CH 2 F, -CH 2 -cyclopropyl, -CH 2 - cyclobutyl, cyclopropyl, cyclobutyl and cyclopentyl, Where R 11 The cyclopropyl, cyclobutyl or cyclopentyl represented by the present invention is optionally substituted by one or two independently selected from D, F, C 1-3 Alkoxy and C 1-3 The definitions of the remaining variables are provided in any of the first aspect or the first to twentieth embodiments or any alternative embodiments described therein. In some embodiments, R 11 is cyclopropyl, the cyclopropyl being optionally substituted by one to two independently selected from F and C 1-3 The alkyl group is substituted with a substituent.

[0149] In an alternative twenty-first embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to twentieth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 11 is independently selected at each occurrence from F, -C(=O)CH 3 、-C(=O)CH 2 CH 3 , -C(=O)cyclopropyl, -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 3 , cyclopropyl and cyclobutyl; wherein R 11 The cyclopropyl represented by is optionally substituted by one to two independently selected from F and C 1-3 The definitions of the remaining variables are provided in the first aspect or any one of the first to twentieth embodiments. In some embodiments, R 11 is cyclopropyl, the cyclopropyl being optionally substituted by one to two independently selected from F and C 1-3 Substituents on the alkyl group are substituted with, or are any of the alternative embodiments described therein.

[0150] In the twenty-second embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-first embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 Is H or C 1-3 Alkyl, and R 10 It is H, C 3-6 Cycloalkyl or C 1-3 Alkyl. The definitions for the remaining variables are provided in the first aspect or any one of the first through twenty-first embodiments, or any alternative embodiments described therein.

[0151] In an alternative twenty-second embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-first embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 Each independently is H or C 1-3 Alkyl. The definitions for the remaining variables are provided in the first aspect or any one of the first through twenty-first embodiments, or any alternative embodiments described therein.

[0152] In the twenty-third embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-second embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 is H or –CH 3 , and R 10 is H, cyclopropyl or -CH 3 The definitions of the remaining variables are provided in the first aspect or any one of the first through twenty-second embodiments, or any alternative embodiments described therein.

[0153] In an alternative twenty-third embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to twenty-second embodiments, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 are each independently H or -CH 3 Alkyl. The definitions for the remaining variables are provided in the first aspect or any one of the first through twenty-second embodiments, or any alternative embodiments described therein.

[0154] In the twenty-fourth embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to twenty-third embodiments, or a pharmaceutically acceptable salt thereof, wherein B is phenyl, naphthyl or 8 to 10 membered bicyclic heteroaryl; wherein the phenyl, naphthyl and 8 to 10 membered bicyclic heteroaryl represented by B are optionally replaced by one to three R 8 The definitions of the remaining variables are provided in the first aspect or any one of the first through twenty-third embodiments, or any alternative embodiments described therein.

[0155] In the twenty-fifth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-fourth embodiments, or a pharmaceutically acceptable salt thereof, wherein B is optionally substituted by one to three R 8 Substituted 9- or 10-membered bicyclic heteroaryl. The definitions of the remaining variables are provided in the first aspect or any one of the first through twenty-fourth embodiments or any alternative embodiments described therein.

[0156] In an alternative twenty-fifth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-fourth embodiments, or a pharmaceutically acceptable salt thereof, wherein B is optionally substituted by one to three R 8 Substituted 9-membered bicyclic heteroaryl. The definitions of the remaining variables are provided in the first aspect or any one of the first through twenty-fourth embodiments or any alternative embodiments described therein.

[0157] In a twenty-sixth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-third embodiments, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of phenyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, benzotriazolyl, imidazopyrazinyl, benzoxazolyl, triazolopyridinyl, benzisothiazolyl, pyrazolopyridinyl, pyrazolopyrazinyl, pyrazolopyrimidinyl, thienopyridinyl, thienopyrimidinyl, benzothiazolyl, pyrrolopyridinyl, pyrrolopyrazinyl, benzofuranyl, benzothienyl, isoquinolinyl, pyrrolotriazinyl, thienopyridinyl, triazolopyridazinyl, benzoxadiazolyl, indolyl, indolin-2-onyl, furopyridine, benzimidazolyl, benzothiadiazole, phthalazinyl and phthalazin-1-onyl, each of which is optionally replaced by one to three R 8 replace; or

[0158] B is 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onyl, each of which is optionally substituted by C 1-3 Alkyl substituted. The definitions for the remaining variables are provided in the first aspect or any one of the first through twenty-third embodiments, or any alternative embodiments described therein.

[0159] In an alternative twenty-sixth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-third embodiments, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of phenyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, benzotriazolyl, imidazopyrazinyl, benzoxazolyl, triazolopyridinyl, benzisothiazolyl, pyrazolopyridinyl, thienopyridinyl, benzothiazolyl, pyrrolopyridinyl, pyrrolopyrazinyl, benzofuranyl, benzothienyl, thienopyridinyl, triazolopyridazinyl, benzoxadiazolyl, indolyl, indolin-2-onyl, furopyridine, benzimidazolyl, benzothiadiazole, phthalazinyl and phthalazin-1-onyl, each of which is optionally substituted by one to three R 8 replace; or

[0160] B is 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onyl, each of which is optionally substituted by C 1-3 Alkyl substituted. The definitions for the remaining variables are provided in the first aspect or any one of the first through twenty-third embodiments, or any alternative embodiments described therein.

[0161] In the twenty-seventh embodiment, the present disclosure provides a compound according to the twenty-sixth embodiment, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of:

[0162] Each of which is optionally replaced by one to three R 8 replace; or

[0163] B is Definitions for the remaining variables are provided in the twenty-sixth embodiment or any alternative embodiment described therein.

[0164] In an alternative twenty-seventh embodiment, the present disclosure provides a compound according to the twenty-sixth embodiment, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of:

[0165] Each of which is optionally replaced by one to three R 8 replace; or

[0166] B is Definitions for the remaining variables are provided in the twenty-sixth embodiment or any alternative embodiment described therein.

[0167] In the twenty-eighth embodiment, the present disclosure provides a compound according to any one of the first aspect or the first to twenty-seventh embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8Each occurrence is halogenated, -CN, -OH, C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-2 Haloalkyl or C 1-2 Alkoxy. The definitions for the remaining variables are provided in the first aspect or any one of the first through twenty-seventh embodiments, or any alternative embodiments described therein.

[0168] In an alternative twenty-eighth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-seventh embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8 Each occurrence is halogenated, -CN, -OH, C 1-3 Alkyl, C 1-2 Haloalkyl or C 1-2 Alkoxy. The definitions for the remaining variables are provided in the first aspect or any one of the first through twenty-seventh embodiments, or any alternative embodiments described therein.

[0169] In the twenty-ninth embodiment, the present disclosure provides a compound according to the twenty-eighth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 8 is independently selected at each occurrence from -F, -Cl, -Br, -CN, -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 , -CHF 2 , -CF 3 、-OH、-OCH 3 、-OCH 2 CH 3 The definitions of the remaining variables are provided as in the twenty-eighth embodiment or any alternative embodiment described therein.

[0170] In an alternative twenty-ninth embodiment, the present disclosure provides a compound according to the twenty-eighth embodiment, or a pharmaceutically acceptable salt thereof, wherein R 8 is independently selected at each occurrence from -F, -Cl, -CN, -CH 3 、-CH 2 CH 3 、-CH(CH 3 ) 2 , -CHF 2 、-OH、-OCH 3 and -OCH 2 CH 3 The definitions of the remaining variables are provided in the twenty-eighth embodiment or any alternative embodiment described therein.

[0171] In the thirtieth embodiment, the present disclosure provides a compound according to the first aspect or any one of the first to twenty-ninth embodiments, or a pharmaceutically acceptable salt thereof, wherein R 8a -CH in each occurrence 3 or -CH 2 CH 3； And R 8b In each occurrence is –CH 3 The definitions for the remaining variables are provided in the first aspect or any one of the first through twenty-ninth embodiments or any alternative embodiments described therein.

[0172] In a thirty-first embodiment, the present disclosure provides a compound according to the first aspect or the first embodiment, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula:

[0173]

[0174] or a pharmaceutically acceptable salt thereof, wherein:

[0175] R 5 It is halogenated;

[0176] R 6 It is A, -NH-C(=O)-A, -C(=O)NH-A or -NH-A;

[0177] R 7 It is B;

[0178] A is a 4- to 6-membered monocyclic saturated heterocyclic group, a 6- to 10-membered bicyclic saturated fused or spiro heterocyclic group, or C 3-6 The 4- to 6-membered monocyclic saturated heterocyclic group and the 6- to 10-membered bicyclic saturated fused or spiro heterocyclic group are each optionally substituted by 1 or 2 R 11 Replaced, and the C 3-6 Cycloalkyl is -NR 9 R 10 and optionally further substituted by R 11 replace;

[0179] R 9 and R 10 Each independently is H or C 1-3 alkyl;

[0180] Each R 11 Independently C 1-3 Alkyl or C 3-6 Cycloalkyl,

[0181] B is optionally replaced by 1 to 3 R 8substituted 9-membered bicyclic heteroaryl, wherein the 9-membered bicyclic heteroaryl has 2 to 4 N ring atoms; and

[0182] Each R 8 Independently C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy.

[0183] In a thirty-second embodiment, the present disclosure provides a compound according to the thirty-first embodiment, or a pharmaceutically acceptable salt thereof, as defined in, wherein:

[0184] R 5 It is F;

[0185] A is cyclobutyl or Het, wherein Het is azetidinyl, piperidinyl, 3-azabicyclo[3.1.0]hexyl, 2,8-diazaspiro[4.5]decyl or 2,7-azaspiro[3.5]nonyl, each of which is optionally substituted by C 1-3 Alkyl or C 3-6 A is substituted with a cycloalkyl group, and the cyclobutyl group represented by A is optionally replaced by -NR 9 R 10 replace;

[0186] R 9 and R 10 Each is H or –CH 3 ;

[0187] B is represented by the following formula:

[0188] Each of which is optionally replaced by 1 or 2 R 8 replace; and

[0189] Each R 8 Independently C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Definitions of the remaining variables are provided in the thirty-first embodiment.

[0190] In the thirty-third embodiment, the present disclosure provides a compound according to the thirty-first or thirty-second embodiment, or a pharmaceutically acceptable salt thereof, wherein A is represented by the following formula:

[0191]

[0192] Each of which is optionally C 1-3 Alkyl substituted. The definitions of the remaining variables are provided in the thirty-first or thirty-second embodiment.

[0193] In the thirty-fourth embodiment, the present disclosure provides a compound according to any one of the thirty-first, thirty-second and thirty-third embodiments, or a pharmaceutically acceptable salt thereof, wherein A is represented by the formula:

[0194] Definitions of the remaining variables are provided in the thirty-first, thirty-second, or thirty-third embodiment.

[0195] In the thirty-fifth embodiment, the present disclosure provides a compound according to any one of the thirty-first to thirty-fourth embodiments, or a pharmaceutically acceptable salt thereof, wherein B is represented by the formula:

[0196] Definitions for the remaining variables are provided in the thirty-first, thirty-second, thirty-third, or thirty-fourth embodiment.

[0197] In the thirty-sixth embodiment, the present disclosure provides a compound according to any one of the thirty-first to thirty-fifth embodiments, or a pharmaceutically acceptable salt thereof, wherein each R 8 Yes – CH 3 , –CHF 2 CF 3 or –OCH 3 Definitions of the remaining variables are provided in the thirty-first, thirty-second, thirty-third, thirty-fourth or thirty-fifth embodiment.

[0198] In one embodiment, the present disclosure provides a compound selected from the compounds disclosed in the Examples and Table 1, a pharmaceutically acceptable salt or a stereoisomer thereof.

[0199] Table 1

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287] *Stereochemistry is arbitrarily assigned 2. Definitions As used herein, the term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0288] The term "alkyl" used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl" refers to a radical of the formula -C n H (2n+1) The alkyl group is a saturated aliphatic straight or branched monovalent hydrocarbon group. Unless otherwise specified, the alkyl group generally has 1-20, 1-10, or 1-6 carbon atoms. In some embodiments, the alkyl group has 1-6 carbon atoms, i.e., C 1-6 As used herein, "C 1-6 "Alkyl" refers to a group having 1 to 6 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, and the like. In some embodiments, the alkyl group has 1-4 carbon atoms, i.e., C 1-4 In some embodiments, the alkyl group has 1 to 3 carbon atoms, i.e., C 1-3 alkyl.

[0289] As used herein, the term "alkoxy" or "alkoxyl" refers to an O-alkyl group, wherein alkyl is as defined above.

[0290] The term "haloalkyl" refers to an alkyl group substituted by one or more halogen atoms as appropriate. In one embodiment, the alkyl group may be substituted by one to three halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, etc.

[0291] As used herein, the term "alkylene" refers to a group of the formula -C n H 2n -a straight or branched divalent hydrocarbon group. Non-limiting examples include ethylene and propylene.

[0292] The term "carbocyclyl" refers to any stable non-aromatic hydrocarbon ring with 3-12 membered carbocyclyls. In one embodiment, carbocyclyl is a 3-, 4-, 5-, 6-, 7- or 8-membered monocyclic or bicyclic hydrocarbon ring, or a 7-, 8-, 9-, 10-, 11- or 12-membered bicyclic or tricyclic hydrocarbon ring, any of which can be saturated, partially unsaturated or unsaturated. Any substitutable ring atom can be substituted (e.g., substituted by one or more substituents). Examples of these carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl and cyclooctadienyl. In one embodiment, carbocyclyl is intended to include bridged rings, fused rings and spirocyclic rings. In spirocyclic carbocyclyl, there is an atom shared by two different rings. An example of spirocyclic carbocyclyl is spiro[3.3]heptyl. In a bridged carbocyclyl, the rings share at least two common non-adjacent atoms. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptyl, bicyclo[2.2.1]hept-2-enyl, and adamantyl. In a fused-ring carbocyclyl system, two or more rings may be fused together so that the two rings share a common bond. Examples of di-fused-ring or tri-fused-ring carbocyclyls include naphthyl, tetrahydronaphthyl (tetralinyl), indenyl, indanyl (dihydroindenyl), anthracenyl, phenanthrenyl, and decahydronaphthyl.

[0293] The term "bridged carbocyclyl" refers to a 5- to 12-membered polycyclic carbocyclyl group, wherein any two rings in the group share two non-connected atoms, the rings may have one or more double bonds, but no completely conjugated π-electron system. Representative examples of bridged carbocyclyl groups include, but are not limited to, the following groups:

[0294]

[0295] The term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic or polycyclic saturated hydrocarbon group with 3 to 12 ring carbons. In one embodiment, the cycloalkyl can have 3 to 7 or 3 to 6 ring carbons. Any substitutable ring atom can be substituted (e.g., substituted by one or more substituents). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkyl can include multiple fused rings and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyls include: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyls also include spirocycles (e.g., spirocyclic bicycles where the two rings are joined by only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like.

[0296] The term "heterocyclyl" or "heterocyclic" refers to a group of a 3-12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur, including sulfoxides and sulfones ("3-12-membered heterocyclyl"). In some embodiments, the heterocyclyl is a 3-7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-7-membered heterocyclyl"). In heterocyclyls containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, as long as the valence permits. The heterocyclyl can be a monocyclic system ("monocyclic heterocyclyl"), or a polycyclic system (e.g., a bicyclic system ("bicyclic heterocyclyl"), or a tricyclic system ("tricyclic heterocyclyl"); polycyclic systems include fused, bridged, or spirocyclic systems). Exemplary monocyclic heterocyclyls include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxetanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems may include heteroatoms in one or more rings in the polycyclic ring system. Substituents may be present on one or more rings in the polycyclic ring system.

[0297] Spiroheterocyclyl refers to a 5- to 12-membered polycyclic heterocyclic radical whose rings are linked together by a common carbon atom (called a spiro atom), wherein the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones), and the remaining ring atoms are C, wherein one or more rings may contain one or more double bonds, but none of the rings have a completely conjugated π electron system. Representative examples of spiroheterocyclyl include, but are not limited to, the following groups:

[0298]

[0299] Fused heterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl, wherein each ring in the group shares a pair of adjacent carbon atoms with another ring in the group, wherein one or more rings may contain one or more double bonds, but none of the rings have a completely conjugated π electron system, and wherein the ring has one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones), and the remaining ring atoms are C. Representative examples of fused heterocyclyls include, but are not limited to, the following groups:

[0300]

[0301] Bridged heterocyclyl refers to a 5- to 12-membered polycyclic heterocyclyl group, wherein any two rings in the group share two non-connected atoms, the rings may have one or more double bonds, but do not have a completely conjugated π electron system, and the rings have one or more heteroatoms selected from the group consisting of nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones) as ring atoms, and the remaining ring atoms are C. Representative examples of bridged heterocyclyl groups include, but are not limited to, the following groups:

[0302]

[0303] In general, carbocyclyl, cycloalkyl or heterocyclyl can be unsubstituted or, when valence permits, substituted with one or more substituents, wherein the substituents can be independently selected from a plurality of groups. Exemplary substituents include, but are not limited to, oxo, -CN, halogen, alkyl and alkoxy, and optionally, the alkyl substituent can be further substituted.

[0304] The term "aryl" refers to a 6- to 10-membered all-carbon monocyclic or polycyclic fused ring (a "fused" ring system means that each ring in the system shares a pair of adjacent carbon atoms with the other rings in the system) group, and has a completely conjugated π electron system. The term "aryl" can be used interchangeably with the terms "aromatic ring", "carbocyclic aromatic ring", "aryl" and "carbocyclic aromatic group". Representative examples of aryl are phenyl and naphthyl.

[0305] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic (eg, bicyclic) aromatic hydrocarbon in which at least one ring carbon atom has been replaced by a heteroatom independently selected from oxygen, nitrogen and sulfur. Preferably, the heteroaryl is based on C 5-10 Aryl, wherein one or more ring carbon atoms are replaced by heteroatoms. Heteroaryl groups may be attached via ring carbon atoms or, when valence permits, via ring nitrogen atoms. In general, heteroaryl groups may be unsubstituted or, when valence permits, substituted with one or more substituents. Exemplary substituents include, but are not limited to, halogen, OH, alkyl, alkoxy, and amino (e.g., NH 2 、NH alkyl、N(alkyl) 2 ), optionally, the alkyl group may be further substituted.

[0306] Examples of monocyclic 5-6 membered heteroaryl groups include furanyl (e.g., 2-furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5-oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1 The polycyclic aromatic heteroaryl groups include carbazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, indolyl, quinolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolyl, indolyl, isoindolyl, acridinyl, or benzisoxazolyl. "Substituted heteroaryl" is substituted at any one or more substitutable ring atoms which are ring carbon atoms or ring nitrogen atoms bonded to a hydrogen.

[0307] As used herein, many moieties (e.g., alkyl, alkylene, cycloalkyl, aryl, heteroaryl, or heterocyclyl) are referred to as "substituted" or "optionally substituted." When one of these terms is used to modify a moiety, unless otherwise indicated, it means that any portion of the moiety known to those skilled in the art to be available for substitution can be substituted, including one or more substituents. If more than one substituent is present, each substituent can be independently selected. Such substitution methods are well known in the art and / or taught by the present disclosure. An optional substituent can be any substituent suitable for attachment to the moiety.

[0308] When suitable substituents are not specifically listed, exemplary substituents include, but are not limited to: 1-5 Alkyl, C 1-5 Hydroxyalkyl, C 1-5 Haloalkyl, C 1-5 Alkoxy, C 1-5 Haloalkoxy, halogen, hydroxy, cyano, amino, -CN, -NO 2 、-OR c1 、-NR a1 R b1 、-S(O) i R a1 、-NR a1 S(O) i R b1 、-S(O) i NR a1 R b1 、-C(=O)OR a1 、-OC(=O)OR a1 、-C(=S)OR a1 、-O(C=S)R a1 、-C(=O)NR a1 R b1 、-NR a1 C(=O)R b1 、-C(=S)NR a1 R b1 、-C(=O)R a1 、-C(=S)R a1 NR a1 C(=S)R b1 、-O(C=O)NR a1 R b1 、-NR a1 (C=S)OR b1 、-O(C=S)NR a1 R b1 、-NR a1 (C=O)NR a1 R b1 、-NR a1 (C=S)NR a1 R b1 , phenyl or 5-6 membered heteroaryl. Each R a1 and each R b1 Independently selected from -H and C 1-5 Alkyl, the alkyl group is optionally substituted by hydroxyl or C 1-3 Alkoxy substituted; R c1 Yes - H, C 1-5 Haloalkyl or C 1-5 Alkyl, wherein the C 1-5The alkyl group is optionally replaced by a hydroxyl group or a C 1 -C 3 Alkoxy substitution.

[0309] As used herein, the notation Refers to the points where parts are connected.

[0310] Pharmaceutically acceptable salts

[0311] The term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation and allergic response, and is commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0312] Pharmaceutically acceptable salts of the compounds of any of the above formulae include acid addition salts and base salts.

[0313] The present teachings include pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts with one or more pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and salts of organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present teachings having an acidic group (e.g., carboxylic acid) can form pharmaceutically acceptable salts with one or more pharmaceutically acceptable bases. Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (e.g., sodium salts and potassium salts), and alkaline earth metal salts (e.g., magnesium salts and calcium salts).

[0314] The pharmaceutically acceptable salts of the compounds of any of the above formulae can be prepared by one or more of the following three methods:

[0315] (i) by reacting a compound of any of the above formulae with a desired acid or base;

[0316] (ii) by removing an acid-labile or base-labile protecting group from a suitable precursor of a compound of any of the above formulae, or by ring-opening a suitable cyclic precursor (e.g., a lactone or lactam) using the desired acid or base; or

[0317] (iii) converting one salt of a compound of any of the above formulae into another salt by reacting the salt with a suitable acid or base or with the aid of a suitable ion exchange column.

[0318] All three reactions are usually carried out in solution. The resulting salt may precipitate and be collected by filtration, or it may be recovered by evaporation of the solvent. The degree of ionization of the resulting salt may vary from fully ionized to almost non-ionized.

[0319] The compounds of any of the above formulae and their pharmaceutically acceptable salts may exist in unsolvated and solvated forms.

[0320] Stereoisomers and other variants

[0321] Compounds of any of the above formulae may exhibit one or more isomerisms (e.g., optical isomerism, geometric isomerism, or tautomerism). Such variations are unambiguous for compounds of any of the above formulae, as they are defined by reference to their structural features and are therefore within the scope of the present disclosure.

[0322] Compounds with one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have either the R configuration or the S configuration, or can be a mixture of the two. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers that are not identical and are not mirror images of each other, and they have two or more chiral centers.

[0323] When a compound is named in its chemical name (e.g., when "R" or "S" is used in the chemical name to indicate configuration) or in its structure (e.g., when a "wedge-shaped" bond is used to indicate configuration) to indicate a single enantiomer, unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "enantiomerically pure"). The optical purity is the weight of the named or depicted enantiomer in the mixture divided by the total weight of the mixture of two enantiomers.

[0324] When the stereochemistry of a disclosed compound is named or depicted by a structure and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is understood to include one encompassed stereoisomer or any mixture of encompassed stereoisomers. It is also understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, the stereoisomeric purity is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0325] When two stereoisomers are depicted in their chemical names or structures and connected with "and" between the chemical names or structures, a mixture of the two stereoisomers is intended.

[0326] When two stereoisomers are depicted in their chemical names or structures, and the names or structures are linked with "and", it is intended to refer to one or the other of the two stereoisomers, but not both.

[0327] When a disclosed compound having a chiral center is depicted by a structure, but the configuration of the chiral center is not shown, the structure is intended to include compounds in the S configuration at the chiral center, compounds in the R configuration at the chiral center, or compounds in a mixture of R and S configurations at the chiral center. When a disclosed compound having a chiral center is depicted by its chemical name, but without indicating whether the chiral center is in the "S" or "R" configuration, the name is intended to encompass compounds in the S configuration at the chiral center, compounds in the R configuration at the chiral center, or compounds in a mixture of R and S configurations at the chiral center.

[0328] A racemic mixture refers to 50% of one enantiomer and 50% of the corresponding enantiomer. When a compound having one chiral center is named or depicted, but the stereochemistry of the chiral center is not shown, it is understood that the name or structure encompasses both possible enantiomeric forms of the compound (e.g., enantiomerically pure, enantiomerically enriched, or racemic forms). When a compound having two or more chiral centers is named or described, but the stereochemistry of the chiral center is not shown, it is understood that the name or structure encompasses all possible diastereomeric forms of the compound (e.g., diastereomerically pure, diastereomerically enriched, and equimolar mixtures of one or more diastereomers (e.g., racemic mixtures).

[0329] The term "geometric isomer" refers to isomers that differ in the orientation of substituent atoms relative to a carbon-carbon double bond, a carbocyclic ring, or a bridged bicyclic ring system. Substituent atoms (except hydrogen) on either side of a carbon-carbon double bond can be in either the E or Z configuration according to the Cahn-Ingold-Prelog priority rules. In the "E" configuration, the substituents with the highest priority are on opposite sides of the carbon-carbon double bond. In the "Z" configuration, the substituents with the highest orientation priority are on the same side of the carbon-carbon double bond.

[0330] Substituents around a carbon-carbon double bond may also be referred to as "cis" or "trans," where "cis" means that the substituents are on the same side of the double bond, and "trans" means that the substituents are on opposite sides of the double bond. Arrangements of substituents around a carbon ring may also be designated as "cis" or "trans." The term "cis" means that the substituents are on the same side of the plane of the ring, while the term "trans" means that the substituents are on opposite sides of the plane of the ring. A mixture of compounds in which substituents are placed on both the same side and opposite sides of the plane of the ring is designated "cis / trans."

[0331] Tautomerism ("tautomerism") occurs when structural isomers can be interconverted across a low energy barrier. This can result in proton tautomeric forms for compounds of any of the above formulae containing, for example, an imino, keto or oxime group, or so-called valence tautomeric forms for compounds containing aromatic moieties. Thus, a single compound may exhibit multiple types of isomers.

[0332] In some cases, there are tautomeric forms of the disclosed compounds, such as the tautomeric structures shown below:

[0333]

[0334] When geometric isomers are depicted by name or structure, it is understood that the named or depicted isomer is present to a greater extent than the other isomer, that is, the geometric purity of the named or depicted geometric isomer is greater than 50%, for example, at least 60%, 70%, 80%, 90%, 99% or 99.9% pure by weight. Geometric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all geometric isomers in the mixture.

[0335] Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0336] Conventional techniques for preparing / isolating individual enantiomers / diastereomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound (e.g., an alcohol), or, in the case of a compound of any of the above formulas containing an acidic or basic moiety, with a base or acid (e.g., 1-phenylethylamine or tartaric acid). The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization, and one or both diastereomers may be converted to the corresponding pure enantiomer by methods well known to those skilled in the art. A chiral compound of any of the above formulae (and its chiral precursor) can be obtained in an enantiomerically enriched form on an asymmetric resin using chromatography (typically HPLC), wherein the mobile phase consists of a hydrocarbon (typically heptane or hexane) containing 0 to 50% by volume of isopropanol (typically 2% to 20%) and 0 to 5% by volume of an alkylamine (typically 0.1% diethylamine). The eluent is concentrated to obtain an enriched mixture. Chiral chromatography using subcritical and supercritical fluids can be used. Chiral chromatography that can be used in some embodiments of the present disclosure is known in the art (see, for example, Smith, Roger M., Loughborough University, Loughborough, UK; Chromatographic Science Series (1998), 75 (Supercritical Fluid Chromatography with Packed Columns), pages 223-249 and references cited therein). Chromatographic columns can be obtained from Chiral Technologies, Inc. of West Chester, Pa., USA (located in Tokyo, Japan). Chemical Industries, Ltd. subsidiary).

[0337] It must be emphasized that compounds of any of the above formulae are drawn herein in a single tautomeric form and that all possible tautomeric forms are included within the scope of the present disclosure.

[0338] 3. Administration and Dosage

[0339] Typically, the compounds of the present disclosure are administered in an amount effective to treat the disorders described herein. The compounds of the present disclosure can be administered in the form of the compounds themselves, or in the form of pharmaceutically acceptable salts. For the purposes of administration and dosage, the compounds themselves or their pharmaceutically acceptable salts will be referred to as compounds of the present disclosure.

[0340] The compounds of the present disclosure may be administered by any suitable route in the form of a pharmaceutical composition suitable for such route and in a dose effective for the intended treatment. The compounds of the present disclosure may be administered orally, rectally, vaginally, parenterally or topically.

[0341] The compounds of the present disclosure can be administered orally. Oral administration can involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration can be employed, in which case the compound enters the bloodstream directly from the mouth.

[0342] In another embodiment, the compounds of the present disclosure can also be directly administered to the bloodstream, muscle or internal organs. Suitable modes for parenteral administration include, for example, intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes and infusion techniques.

[0343] In another embodiment, the compounds of the present disclosure may also be topically applied to or to the skin or mucous membrane, i.e., transdermally or transdermally. In another embodiment, the compounds of the present disclosure may also be administered intranasally or by inhalation. In another embodiment, the compounds of the present disclosure may be administered rectally or vaginally. In another embodiment, the compounds of the present disclosure may also be directly applied to the eyes or ears.

[0344] The dosage regimen of the disclosed compounds and / or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex, and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound used. Therefore, the dosage regimen may vary greatly. In one embodiment, the total daily dose of the disclosed compounds for treating the indications discussed herein is typically about 0.001 to about 100 mg / kg (i.e., mg of the disclosed compound / kg body weight).

[0345] For oral administration, the composition can be provided in the form of tablets containing 0.1-500 mg of active ingredient, and this dosage can be adjusted according to the patient's symptoms. One medicament usually contains about 0.01 mg to about 500 mg of active ingredient. When administered intravenously, the dosage range can be about 0.01 to about 10 mg / kg / min during infusion at a constant rate.

[0346] Suitable subjects according to the present disclosure include mammalian subjects, including non-human mammals, such as primates, rodents (mice, rats, hamsters, rabbits, etc.). In one embodiment, humans are suitable subjects. Human subjects can be of any gender and are at any stage of development.

[0347] 4. Pharmaceutical Composition

[0348] In another embodiment, the present disclosure includes a pharmaceutical composition. The pharmaceutical composition comprises a provided compound of the present disclosure, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient. Other pharmacologically active substances may also be present.

[0349] As used herein, "pharmaceutically acceptable carriers or excipients" include any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof, and isotonic agents, such as sugars, sodium chloride, or polyols, such as mannitol or sorbitol, may be included in the composition. Pharmaceutically acceptable substances, such as wetting agents or small amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives, or buffers, will extend the shelf life or effectiveness of the antibody or antibody portion.

[0350] Compositions of the present disclosure can be in various forms. These include, for example, liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The form depends on the intended mode of administration and therapeutic application.

[0351] Typical compositions are in the form of injectable or infusible solutions, such as compositions similar to those commonly used for passive immunization of humans with antibodies. One mode of administration is parenteral administration (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular administration). In another embodiment, the antibody is administered by intravenous infusion or injection. In another embodiment, the antibody is administered by intramuscular or subcutaneous injection.

[0352] Oral administration of solid dosage forms can be presented, for example, in discrete units, such as hard or soft capsules, pills, cachets, buccal tablets or tablets, each unit containing a predetermined amount of at least one compound of the present disclosure. In another embodiment, oral administration can be in the form of a powder or granules. In another embodiment, the oral dosage form is a sublingual dosage form, such as a buccal tablet. In such solid dosage forms, the compound of any of the above formulas is typically combined with one or more adjuvants. Such capsules or tablets may contain a controlled release formulation. In the case of capsules, tablets and pills, the dosage form may also contain a buffer, or may be prepared to have an enteric coating.

[0353] In another embodiment, oral administration can be a liquid dosage form. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, which contain inert diluents commonly used in the art (e.g., water). Such compositions may also include adjuvants, such as wetting agents, emulsifiers, suspending agents, flavoring agents (e.g., sweeteners) and / or aromatics.

[0354] In another embodiment, the present disclosure encompasses parenteral dosage forms.

[0355] "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (such as sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using suitable dispersants, wetting agents and / or suspending agents.

[0356] In another embodiment, the present disclosure comprises a topical dosage form.

[0357] "Topical application" includes, for example, transdermal administration, such as by transdermal patches or iontophoresis devices, intraocular administration, or intranasal or inhaled administration. Compositions for topical application also include, for example, topical gels, sprays, ointments and creams. Topical preparations may include compounds that enhance the absorption or penetration of active ingredients through the skin or other affected areas. When the compounds of the present disclosure are applied by transdermal devices, the application will be achieved using reservoir-type and porous membrane-type or solid matrix-type patches. Typical preparations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, talcum powders, dressings, foams, membranes, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerol, polyethylene glycol and propylene glycol. Permeation enhancers may be incorporated, see, eg, Finnin and Morgan, J. Pharm. Sci., 88:955-958, 1999.

[0358] Preparations suitable for topical application to eyes include, for example, eye drops, in which the compounds of the present disclosure are dissolved or suspended in a suitable carrier. Typical preparations suitable for eye or ear administration can be in the form of drops of micronized suspensions or solutions in isotonic sterile saline with adjusted pH. Other preparations suitable for eye and ear administration include ointments, biodegradable (i.e., absorbable gel sponges, collagen) and non-biodegradable (i.e., silica gel) implants, wafers, lenses and particles or vesicle systems, such as vesicles or liposomes. Polymers can be incorporated with preservatives (e.g., benzalkonium chloride), such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose or methylcellulose) or heteropolysaccharide polymers (e.g., gellan gum). Such preparations can also be delivered by iontophoresis.

[0359] For intranasal administration or administration by inhalation, the disclosed compounds are preferably delivered in the form of solutions or suspensions, squeezed or pumped by the patient through a pump spray container, or delivered from a pressurized container or atomizer using a suitable propellant in an aerosol spray form. Preparations suitable for intranasal administration are usually administered in dry powder form (alone, in a mixture form, such as a dry blend with lactose, or in a mixed component granular form, such as mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler, or in an aerosol spray form from a pressurized container, pump, sprayer, atomizer (preferably using an electrohydrodynamic sprayer to produce a fine mist) or atomizer, with or without a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, powders may include bioadhesives, such as chitosan or cyclodextrin.

[0360] In another embodiment, the present disclosure includes a rectal dosage form. Such a rectal dosage form can be, for example, in the form of a suppository. Cocoa butter is a traditional suppository base, but various substitutes can also be used as desired.

[0361] Other carrier materials and modes of administration known in the pharmaceutical art may also be used.The pharmaceutical compositions of the present disclosure may be prepared by any well-known pharmaceutical techniques, such as effective formulation and administration procedures.

[0362] The above considerations regarding effective formulation and administration procedures are well known in the art and are described in standard textbooks. Pharmaceutical formulations are discussed in, for example, Hoove r, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa., 1975; Liberman et al., ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., ed., Handbook of Pharmaceutical Excipients (3rd ed.), American Pharma ceutical Association, Washington, 1999.

[0363] 5. Treatment Methods

[0364] The terms "subject," "individual," or "patient" are used interchangeably and mean any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

[0365] The terms "treatment", "treat" and "treating" refer to reversing, alleviating or inhibiting the progression of a disease described herein. In some embodiments, treatment can be administered after one or more signs or symptoms of a disease have developed or been observed (i.e., therapeutic treatment). In other embodiments, treatment can be administered in the absence of signs or symptoms of the disease. For example, treatment can be administered to a susceptible individual (i.e., prophylactic treatment) prior to the onset of symptoms (e.g., based on a history of symptoms and / or based on exposure to a pathogen). Treatment can also be continued after symptoms subside, e.g., to delay or prevent recurrence.

[0366] As used herein, the term "prevention" (or "prevent" or "preventing") refers to excluding, avoiding, eliminating, preventing in advance, reducing the occurrence of a disease, disorder and / or condition, stopping or hindering its symptoms. Prevention includes the administration of a drug to a subject who does not show symptoms of the disease, disorder and / or condition at the time of administration.

[0367] The terms "disease," "disease," and "condition" are used interchangeably.

[0368] The terms "administer", "administering" or "administration" refer to methods of introducing a compound disclosed herein or a composition thereof into or on the body of a patient. These methods include, but are not limited to, intraarticular (in a joint), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal administration, and the like. Administration techniques that can be used with the agents and methods described herein are found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current edition; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0369] In general, the effective amount of the compound taught herein depends on various factors, such as a given drug or compound, pharmaceutical formulation, route of administration, type of disease or condition, identity of the subject or host to be treated, etc., but can still be routinely determined by those skilled in the art. One of ordinary skill in the art can easily determine the effective amount of the compound taught by the present invention by conventional methods known in the art.

[0370] The term "therapeutically effective amount" refers to an amount that produces beneficial or desired results (including clinical results) when administered to a subject, such as an amount that inhibits, suppresses or alleviates the symptoms of the subject's treated disorder compared to a control. The exact amount required will vary from subject to subject, depending on the subject's species, age and general condition, the severity of the disease, the specific anticancer agent, its mode of administration, combined treatment with other therapies, etc.

[0371] The present disclosure relates to compounds of formula (I) (including all embodiments thereof), which are useful for treating and / or preventing diseases and / or conditions associated with or regulated by HTT, particularly where reducing mHTT in a subject has therapeutic benefit, including but not limited to treating and / or preventing HD.

[0372] In one embodiment, the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0373] In one embodiment, the disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body.

[0374] The present disclosure also provides a method for treating HD in a subject in need thereof, the method comprising administering to the subject an effective amount of (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0375] In one embodiment, the present disclosure provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for treating HD in a subject in need thereof, the treatment comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0376] In one embodiment, the disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating HD in a subject in need thereof, the treatment comprising administering to the subject an effective amount of the medicament.

[0377] 6. Treatment kit

[0378] One aspect of the present invention relates to a kit for conveniently and effectively implementing the method or use according to the present invention. In general, a medicine pack or kit comprises one or more containers filled with one or more ingredients of the pharmaceutical composition of the present invention. Such kits are particularly suitable for delivering solid oral dosage forms such as tablets or capsules. Such kits preferably include a plurality of unit doses and may also include a card with the doses arranged in the order of their intended use. If necessary, a memory aid may be provided, for example in the form of numbers, letters or other markings, or with a calendar insert specifying the dates on which the doses may be administered in the treatment plan. The container may optionally be accompanied by a certain form of instructions issued by a government agency that regulates the manufacture, use or sale of the drug product, the instructions reflecting the approval of the agency that manufactures, uses or sells the drug for human administration.

[0379] The following representative examples contain important additional information, illustrations and guidance, which are applicable to various embodiments and equivalents thereof of the present invention. These examples are intended to help illustrate the present invention, but are not intended to, nor should they be interpreted as limiting the scope of the present invention. In fact, it will be apparent to those skilled in the art by reviewing this document (including the following examples and the scientific and patent literature cited herein) that various modifications of the present invention and many other embodiments thereof except those shown and described herein will be apparent.

[0380] The contents of the cited references are incorporated herein by reference to help illustrate the state of the art.

[0381] In addition, for the purpose of the present invention, chemical elements are identified according to the CAS version of the Periodic Table of the Elements (Handbook of Chemistry and Physics, 75th edition, inside cover). In addition, general principles of organic chemistry as well as specific functional moieties and reactivity are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999 and "Organic Chemistry," Morrison & Boyd (3rd edition), the entire contents of both books are incorporated herein by reference.

[0382] 7. Preparation

[0383] The compounds of any of the above formulas can be prepared using the common knowledge of those skilled in the art of synthetic organic chemistry by the general and specific methods described below. Such common knowledge can be found in standard reference books, such as Comprehensive Organic Chemistry, edited by Barton and Ollis, Elsevier; Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Larock, John Wiley and Sons; and Compendium of Organic Synthetic Methods, Vol. I-XII (published by Wiley-Interscience). The starting material used herein is commercially available or can be prepared by conventional methods known in the art.

[0384] When preparing the compound of any of the above formulas, it should be noted that some preparation methods described herein may need to protect the distal functional group (e.g., the precursor of the primary amine, secondary amine, and carboxyl group in any of the above formulas). The demand for such protection will vary depending on the properties of the distal functional group and the conditions of the preparation method. Those skilled in the art can easily determine whether such protection is required. The use of such protection / deprotection methods is also within the skill range of the art. For a general description of protecting groups and their use, refer to Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0385] For example, some compounds contain primary amine or carboxylic acid functional groups, which, if not protected, may interfere with reactions at other sites of the molecule. Therefore, these functional groups may be protected with appropriate protecting groups, which can be removed in subsequent steps. Suitable protecting groups for protecting amines and carboxylic acids include those commonly used in peptide synthesis (e.g., N-tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc) for amines, and lower carbon alkyl or benzyl esters for carboxylic acids), which generally do not react chemically under the described reaction conditions, and can usually be removed without changing the other functional groups in the compounds of any of the above formulae.

[0386] The following scheme is intended to provide a general description of the methods for preparing the disclosed compounds. Certain compounds of the present disclosure may contain single or multiple chiral centers, with stereochemistry designated as (R) or (S). It will be apparent to those skilled in the art that all synthetic transformations can be performed in a similar manner, whether the material is enantiomerically enriched or racemic. In addition, well-known methods described herein and in the chemical literature can also be used to split into the desired optically active material at any desired point in the sequence.

[0387] Example

[0388]

[0389]

[0390] Section 1. General methods and analytical approaches

[0391] a. General Methods

[0392] Unless otherwise described, otherwise according to the analysis of one of the purification process mentioned below or the compound of purification embodiment.When using preparative TLC / HPLC or silica gel chromatography, those skilled in the art can select any solvent combination to purify the desired compound.Use 20-40 μ M (particle diameter), 250-400 mesh or 400-632 mesh silica gel, use Teledyne ISCO Combiflash RF or Grace Reveleris X2 with ELSD purification system, or use pressurized nitrogen (about 10-15psi) to drive solvent to perform silica gel column chromatography by post (" flash chromatography ").Wherein use SCX post, eluent condition is MeOH, followed by methanol ammonia.When pointed out, solution and reaction mixture are concentrated by rotary evaporation under vacuum.

[0393] b. Analytical methods

[0394] Analytical LCMS Instrument Specifications:

[0395] Waters Acquity iClass UPLC with QDa mass spectrometer and PDA (photodiode array detector)

[0396] RxnQC / FrxQC / PurityQC analysis LC / MS method conditions:

[0397] Ammonium Hydroxide (Alkaline pH) Conditions

[0398] Method 1

[0399] MS mode: MS: ESI + scan range 165-650 Daltons

[0400] PDA: 200-400nm scanning range

[0401] Column: Waters ACQUITY UPLC BEH C18 2.1×50 mm, 1.7 um; Part No. 186002350

[0402] Modifier: 0.2% (v / v) ammonium hydroxide

[0403] Method: 95% H 2 O / 5% MeCN (initial condition) for 0.1 min, linear gradient to 5% H 2 O / 95% MeCN,

[0404] 3.25 min, hold at 5% HO 2 O / 95% MeCN to 3.5 minutes. Flow rate, 0.8 mL / min.

[0405] Method 2

[0406] MS mode: MS: ESI + scan range 165-650 Daltons

[0407] PDA: 200-400nm scanning range

[0408] Column: Waters ACQUITY UPLC BEH C18 2.1×30 mm, 1.7 um; Part No. 186002349

[0409] Modifier: 0.2% (v / v) ammonium hydroxide

[0410] Method: 95% H 2 O / 5% MeCN (initial condition), linear gradient to 5% H 2 O / 95% MeCN,

[0411] 1.0 min, hold at 5% HO 2 O / 95% MeCN to 1.3 min. Flow rate, 0.7 mL / min.

[0412] Trifluoroacetic acid (acidic pH) conditions

[0413] Method 3

[0414] MS mode: MS: ESI + scan range 165-650 Daltons

[0415] PDA: 200-400nm scanning range

[0416] Column: Waters ACQUITY UPLC BEH C18 2.1×50 mm, 1.7 um; Part No. 186002350

[0417] Modifier: 0.1% (v / v) trifluoroacetic acid

[0418] Method: 95% H 2 O / 5% MeCN (initial condition) for 0.1 min, linear gradient to 5% H 2 O / 95% MeCN,

[0419] 3.25 min, hold at 5% HO 2 O / 95% MeCN to 3.5 minutes. Flow rate, 0.8 mL / min.

[0420] Method 4

[0421] MS mode: MS: ESI + scan range 165-650 Daltons

[0422] PDA: 200-400nm scanning range

[0423] Column: Waters ACQUITY UPLC BEH C18 2.1×50 mm, 1.7 um; Part No. 186002349

[0424] Modifier: 0.1% (v / v) trifluoroacetic acid

[0425] Method: 95% H 2 O / 5% MeCN (initial condition), linear gradient to 5% H 2 O / 95% MeCN,

[0426] 1.0 min, hold at 5% HO 2 O / 95% MeCN to 1.3 min. Flow rate, 0.7 mL / min.

[0427] Analytical LCMS Instrument Specifications:

[0428] Agilent 1200 Series LC / MSD system, equipped with DAD\ELSD Alltech 3300 and Agilent LC\MSD G6130A, G6120B mass spectrometers; Agilent Technologies 1260 Infinity LC / MSD system, equipped with DAD\ELSD Alltech 3300 and Agilent LC\MSD G6120B mass spectrometers; Agilent Technologies 1260 Infinity II LC / MSD system, equipped with DAD\ELSD G7102A1290 Infinity II and Agilent LC\MSD G6120B mass spectrometers; Agilent 1260 Series LC / MSD system, equipped with DAD\ELSD and Agilent LC\MSD (G6120B) mass spectrometer; UHPLC Agilent 1290 Series LC / MSD system, equipped with DAD\ELSD and Agilent LC\MSD (G6125B) mass spectrometer.

[0429] RxnQC / FrxQC / PurityQC analysis LC / MS method conditions:

[0430] Formic acid (acidic pH) conditions

[0431] Method 5

[0432] Injection volume: 0.5 μl, column temperature: 60 °C, UV scan: 207–223 nM, 246–262 nM, 272–288 nM, Agilent Poroshell 120 SB-C18 4.6 × 30 mm 2.7 μm, equipped with UHPLC Guard Infinity Lab Poroshell120 SB-C18 4.6 × 5 mm 2.7 μm, mobile phase A: water containing 0.1% FA, mobile phase B: acetonitrile containing 0.1% FA

[0433] Elution Details

[0434] Time (minutes) Flow rate (mL / min) ％A ％B 0.00 3.00 99 1 0.01 3.00 99 1 1.5 3.00 0 100 1.73 3.00 0 100 1.74 3.00 99 1

[0435] Method 6

[0436] Injection volume: 0.5 μl; column temperature: 60°C; UV scan: 207–223 nM, 246–262 nM, 272–288 nM

[0437] Agilent Poroshell 120 SB-C18 4.6×30mm 2.7μm, equipped with UHPLC Guard InfinityLab Poroshell 120 SB-C18 4.6×5mm 2.7μm, mobile phase A: water with 0.1% FA, mobile phase B: acetonitrile with 0.1% FA

[0438] Elution Details

[0439] Time (minutes) Flow rate (mL / min) ％A ％B 0.00 1.5 99 1 0.01 1.5 99 1 5.00 1.5 0 100 5.99 1.5 0 100 6.00 1.5 99 1

[0440] Method 7

[0441] MS mode: MS:ESI+ scanning range 100-1000 Daltons

[0442] PDA: 190-370nm scanning range

[0443] Column: Xtimate C18 2.1*30mm, 3um

[0444] Modifier: Phase A: water (4 L) + TFA (1.5 mL), Phase B: acetonitrile (4 L) + TFA (0.75 mL)

[0445] Method: An elution gradient of 10%-80% (Solvent B) was used, the elution time was 1.35 minutes and held at 80% for 0.9 minutes, the flow rate was 0.8 ml / min.

[0446] Method 8

[0447]

[0448] describe:

[0449] Mobile phase: 5% ACN (0.018% TFA) in water (0.037% TFA) to 95% ACN in 3.0 minutes, flow rate set to 1.0 mL / min; then hold at 95% ACN for 0.60 minutes, flow rate set from 1.0 mL / min to 1.5 mL / min; return to 5% ACN in water and hold for 0.40 minutes. Flow rate set to 1.5 mL / min.

[0450] The column temperature was at 50°C.

[0451] The column was Shim-pack Velox SP-C18 2.7 μm 3.0*30 mm.

[0452] Method 9

[0453]

[0454] describe:

[0455] Mobile phase: 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in 0.60 min, flow rate set to 2.0 mL / min; then hold at 95% ACN for 0.18 min, flow rate from 2.0 mL / min; return to 5% ACN in water and hold for 0.02 min. Flow rate set to 2.0 mL / min.

[0456] The column temperature was at 50°C.

[0457] Column is EVO C18 2.1×30mm 5um.

[0458] Method 10

[0459] describe:

[0460] Mobile phase: 5% ACN (0.01875% TFA) in water (0.0375% TFA) to 95% ACN in 3.20 minutes, flow rate set to 1.5 mL / min; then 95% ACN for 0.30 minutes, flow rate from 1.5 mL / min; return to 5% ACN in water and hold for 0.30 minutes. Flow rate set to 2.0 mL / min. Column temperature at 50°C. Column is EVO C18 4.6×50mm 5um.

[0461] Preparative HPLC-MS conditions:

[0462] LCMS Instrument Specifications

[0463] Waters Autopurification with QDa mass spectrometer and PDA (photodiode array detector)

[0464] Ammonium Hydroxide (Alkaline pH) Conditions

[0465] Flow rate: 30mL / min

[0466] MS mode: MS: ESI + scan range 165-650 Daltons

[0467] PDA: 200-400nm scanning range

[0468] Column: Waters XSELECT CSH C18 PREP 19×100mm, 5um; Part No. 186005421

[0469] Modifier: 0.2% (v / v) ammonium hydroxide

[0470] Method: A%H 2 O / B % MeCN (initial conditions) was maintained for 0.5 min, and a linear gradient to A % H 2 O / B % MeCN, increased to 5% H at 8.5 min 2 O / 95% MeCN, maintain 5% H 2 O / 95% MeCN until 10 min.

[0471] Flow rate: 50mL / min

[0472] MS mode: MS: ESI + scan range 165-650 Daltons

[0473] PDA: 200-400nm scanning range

[0474] Column: Waters XSELECT CSH C18 PREP 30×100mm, 5um; Part No. 186005425

[0475] Modifier: 0.2% (v / v) ammonium hydroxide

[0476] Method: A%H 2 O / B % MeCN (initial conditions) was maintained for 0.5 min, and a linear gradient to A % H 2 O / B % MeCN, increased to 5% H at 8.5 min 2 O / 95% MeCN, maintain 5% H 2 O / 95% MeCN until 10 min.

[0477] Flow rate, 60 mL / min

[0478] MS mode: MS: ESI + scan range 165-650 Daltons

[0479] PDA: 200-400nm scanning range

[0480] Column: Waters XSELECT CSH C18 PREP 30×50mm, 5um; Part No. 186005423

[0481] Modifier: 0.2% (v / v) ammonium hydroxide

[0482] Method: A%H 2 O / B % MeCN (initial conditions) was maintained for 0.5 min, and a linear gradient to A % H2 O / B % MeCN, increased to 5% H at 8.5 min 2 O / 95% MeCN, maintain 5% H 2 O / 95% MeCN until 10 min.

[0483] Column: Boston Prime C18 150×30mm×5um; Condition: Water (NH 3 H 2 O+NH 4 HCO 3 )-ACN; gradient (organic %): 0-100%, optimized for each example; flow rate (mL / min): 25.

[0484] Column: YMC Actus Trial C18 20*100 5mkm column; 2 A gradient mixture of O-MeOH-ammonia 0.1% was used as the mobile phase, which was optimized for each example.

[0485] Trifluoroacetic acid (acidic pH) conditions

[0486] Flow rate, 30 mL / min

[0487] MS mode: MS: ESI + scan range 165-650 Daltons

[0488] PDA: 200-400nm scanning range

[0489] Column: Waters Sunfire OBD C18 PREP 19×100mm, 5um; Part No. 186002567

[0490] Modifier: 0.1% (v / v) trifluoroacetic acid

[0491] Method: A%H 2 O / B % MeCN (initial conditions) was maintained for 0.5 min, and a linear gradient to A % H 2 O / B % MeCN, increased to 5% H at 8.5 min 2 O / 95% MeCN, maintain 5% H 2 O / 95% MeCN until 10 min.

[0492] Flow rate, 50 mL / min

[0493] MS mode: MS: ESI + scan range 165-650 Daltons

[0494] PDA: 200-400nm scanning range

[0495] Column: Waters Sunfire OBD C18 PREP 30×100mm, 5um; Part No. 186002572

[0496] Modifier: 0.1% (v / v) trifluoroacetic acid

[0497] Method: A%H 2 O / B % MeCN (initial conditions) was maintained for 0.5 min, and a linear gradient to A % H 2 O / B % MeCN, increased to 5% H at 8.5 min 2 O / 95% MeCN, maintain 5% H 2 O / 95% MeCN until 10 min.

[0498] Flow rate, 60 mL / min

[0499] MS mode: MS: ESI + scan range 165-650 Daltons

[0500] PDA: 200-400nm scanning range

[0501] Column: Waters Sunfire OBD C18 PREP 30×50mm, 5um; Part No. 186002570

[0502] Modifier: 0.1% (v / v) trifluoroacetic acid

[0503] Method: A%H 2 O / B % MeCN (initial conditions) was maintained for 0.5 min, and a linear gradient to A % H 2 O / B % MeCN, increased to 5% H at 8.5 min 2 O / 95% MeCN, maintain 5% H 2 O / 95% MeCN until 10 min.

[0504] Formic acid (FA, acidic pH) conditions

[0505] Column: Welch Xtimate C18 150×30 mm×5 um; Conditions: water (FA)-ACN; Gradient (organic %): optimized for each example; Flow rate (mL / min): 25.

[0506] Hydrochloric acid (HCl, acidic pH) conditions

[0507] Column: Boston Green ODS 150×30 mm×5 um; Conditions: water (HCl)-ACN; Gradient (organic %): 0-100%, optimized for each example; Flow rate (mL / min): 25.

[0508] Analytical SFC Instrument Specifications

[0509] Waters Acquity UPC with QDa mass spectrometer and PDA (photodiode array detector) 2 SFC

[0510] Analysis filter conditions

[0511] MS mode: MS: ESI + scan range 100-650 Daltons

[0512] PDA: 200-400nm scanning range

[0513] Column: See below

[0514] Solvent: Airgas Bone Dry Co 2

[0515] Co-solvent: methanol, ethanol or isopropanol, containing 0.1% diethylamine, 0.1% dimethylethanolamine, or neutral

[0516] Method: Isocratic conditions; typically 60% CO 2 : 40% co-solvent or 70% CO 2 : 30% co-solvent, the flow rate was 3.0 mL / min.

[0517] Preparative SFC Instrument Specifications

[0518] Waters Prep100SFC equipped with QDa mass spectrometer, PDA (photodiode array detector) and 2767 collection bed

[0519] Preparation conditions

[0520] Methods: In CO 2 X% cosolvent in , with Y% modifier, isocratic conditions.

[0521] Flow rate: 100mL / min

[0522] Automatic back pressure regulator: 120 bar

[0523] Manual back pressure regulator: MeOH or EtOH, 40psi; iPrOH, 60psi

[0524] Column box temperature: 40°C

[0525] MS mode: MS: ESI + scan range 150-650 Daltons

[0526] PDA: 200-400nm scanning range

[0527] SFC columns, analytical:

[0528] AD-H: Daicel Chiralpak AD-H, 4.6mm×250mm, 5um, part number 19325

[0529] AS-H: Daicel Chiralpak AS-H, 4.6mm×250mm, 5um, part number 20325

[0530] OD-H: Daicel Chiralpak OD-H, 4.6mm×250mm, 5um, part number 14325

[0531] OX-H: Daicel Chiralpak OX-H, 4.6mm×250mm, 5um, part number 63325

[0532] IA: Daicel Chiralpak IA, 4.6mm×250mm, 5um, part number 80325

[0533] IB: Daicel Chiralpak IB, 4.6mm×250mm, 5um, part number 81325

[0534] IC: Daicel Chiralpak IC, 4.6mm×250mm, 5um, part number 83325

[0535] IG: Daicel Chiralpak IG, 4.6mm×250mm, 5um, part number 87325

[0536] Cell-2: Phenomenex Lux Cellulose-2, 4.6mm×150mm, 3um, part number 00F-4456-E0

[0537] Cell-4: Phenomenex Lux Cellulose-4, 4.6mm×150mm, 3um, part number 00F-4490-E0

[0538] SFC columns, preparative:

[0539] AD-H: Daicel Chiralpak AD-H, 30mm×250mm, 5um, part number 19475

[0540] AS-H: Daicel Chiralpak AS-H, 30mm×250mm, 5um, part number 20475

[0541] OD-H: Daicel Chiralpak OD-H, 30mm×250mm, 5um, part number 14475

[0542] OX-H: Daicel Chiralpak OX-H, 30mm×250mm, 5um, part number 63475

[0543] IA: Daicel Chiralpak IA, 30mm×250mm, 5um, part number 80475

[0544] IB: Daicel Chiralpak IB, 30mm×250mm, 5um, part number 81475

[0545] IC: Daicel Chiralpak IC, 30mm×250mm, 5um, part number 83475

[0546] IG: Daicel Chiralpak IG, 30mm×250mm, 5um, part number 87475

[0547] Cell-2: Phenomenex Lux Cellulose-2, 30mm×250mm, 5um, part number 00G-4457-U0-AX

[0548] Cell-4: Phenomenex Lux Cellulose-4, 30mm×250mm, 5um, part number 00G-4491-U0-AX

[0549] 1 H-NMR

[0550] 1 H nuclear magnetic resonance (NMR) spectra were consistent with the proposed structures in all cases. 1H NMR spectra were recorded on a Bruker Avance III HD 500 MHz, Bruker Avance III 500 MHz, Bruker Avance DRX 500, Bruker Avance III 400 MHz, Varian-400 VNMRS, Varian Unityplus 400, or Varian-400 MR. Characteristic chemical shifts (d) are relative to tetramethylsilane (for 1 H-NMR) are expressed in parts per million downfield, using conventional abbreviations for the major peaks: for example, s, singlet; d, doublet; t, triplet; q, quartet; dd, double doublet; dt, double triplets; m, multiplet; br, broad. Common solvents use the following abbreviations: CDCl 3 , deuterated chloroform; DMSO-d 6 , hexadeuterated dimethyl sulfoxide; MeOH-d 4 , deuterated methanol. Where appropriate, tautomers may be recorded in the NMR data; and some exchangeable protons may not be visible.

[0551] Section 2. Preparation of intermediates

[0552] Intermediate 1

[0553]

[0554] A solution of 5-bromo-3-fluoro-pyridin-2-amine (623.79 mg, 3.27 mmol) and tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (1 g, 3.27 mmol) in water (30 mL) was stirred at 60 ° C for 12 hours. The mixture was concentrated to give a residue, which was purified by flash silica gel chromatography (EtOAc in petroleum ether, 0-25%) to give tert-butyl 4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (900 mg, 2.26 mmol, 69% yield) as a light yellow solid. MS: m / z 297.9 [M+H] + ; 1 H NMR (400MHz, chloroform-d) δppm: 8.03 (s, 1H), 7.34 (d, J = 2.7Hz, 1H), 6.97 (dd, J = 9.5, 1.2Hz, 1H), 4.12-4.27 (m, 2H), 2.79-2.97 (m, 3H), 2.06 (br d,J=13.0Hz,2H),1.64(br dd,J=12.3,2.8Hz,2H),1.43-1.46(m,9H).

[0555] Intermediate 2

[0556]

[0557] To a solution of tert-butyl 4-(6-bromo-8-fluoroimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (4 g, 10.04 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (5.10 g, 20.09 mmol) in dioxane (150 mL) was added cyclopentyl(diphenyl)phosphine dichloromethane dichloropalladium; iron (820.19 mg, 1.00 mmol) and KOAc (2.96 g, 30.13 mmol) and stirred at N 2 Stir at 100 ° C for 48 hours under atmosphere. The mixture was filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (petroleum ether / EtOAc=3 / 1) to give tert-butyl 4-[8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (3.12 g, 7.01 mmol, 69% yield) as a yellow solid. MS: m / z 446.3[M+H] +

[0558] Intermediate 3

[0559]

[0560] To a solution of 5-bromo-3-fluoro-pyridin-2-amine (480 mg, 2.51 mmol) and (2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid (480 mg, 2.51 mmol) in dioxane (5 mL) and water (1 mL) was added K 2 CO 3 (694 mg, 5.03 mmol) and Pd(dppf)Cl 2 (367 mg, 0.50 mmol). The mixture was stirred at 90°C for 16 hours under nitrogen. The mixture was extracted with EtOAc (15 mL x 3) and washed with Na 2 SO 4 Dry. The combined organic phases were filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (40% to 100% EtOAc:PE) to give 5-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-3-fluoro-pyridin-2-amine (446 mg, 1.73 mmol, 68% yield) as a yellow solid. MS: m / z 258.1 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ: 8.48 (s, 1H), 7.97-7.92 (m, 2H), 7.59 (s, 1H), 6.72 (s, 2H), 2.56 (s, 3H), 2.38 (s, 3H).

[0561] Intermediate 4

[0562]

[0563] To a solution of 7-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (3.18 g, 11.52 mmol) in dioxane (60 mL) and water (20 mL) were added 5-bromo-3-fluoropyridin-2-amine (2 g, 10.47 mmol), tripotassium phosphate (4.45 g, 20.94 mmol) and cyclopentyl(diphenyl)phosphinepalladium dichloride; iron (766.18 mg, 1.05 mmol). 2 The mixture was stirred at 100°C for 12 hours under a 37°C atmosphere. The mixture was concentrated and then water (50 mL) was added. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (100 mL) and purified by Na 2 SO 4 Dry, filter and concentrate. The crude material was purified by flash silica gel chromatography (CH 2 Cl 2 :MeOH=100 / 1 to 20 / 1) to obtain 3-fluoro-5-(7-fluoro-2-methyl-2H-indazol-5-yl)pyridin-2-amine (1.77 g, 6.78 mmol, yield 64.72%, purity 99%) as a yellow solid. MS: m / z 261.0 [M+H] + , 1 H NMR (400Hz, DMSO-d6) δ: 8.46 (d, J = 2.8Hz, 1H), 8.17 (d, J = 1.6Hz, 1H), 7.73-7.80 (m, 2H), 7.35-7.39 (m, 1H), 6.33 (s, 2H), 4.20 (s, 3H).

[0564] Intermediate 5

[0565]

[0566] At 25 ° C, a drop of DMF was added to a solution of 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acid (50 mg, 26 umol) in thionyl chloride (3 mL) and stirred at 78 ° C for 1 hour. Then, the mixture was concentrated in vacuo, and the residue was dissolved in THF (5 mL) and acetonitrile (5 mL) and cooled to 0 ° C. Then, diazomethyl(trimethyl)silane (2M, 327 uL) was added to the solution. The mixture was stirred at 0 ° C for 0.5 hours, and then HBr (64 mg, 785 umol) was added at the same temperature and stirred for another 1 hour. Then, the mixture was concentrated in vacuo to give 2-bromo-1-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)ethan-1-one (60 mg, crude product) as a colorless oil, and used directly in the next step. MS: m / z 269.9[M+2H] +

[0567] Intermediate 6

[0568]

[0569] Step a: To a solution of 6-bromo-4-fluoro-2H-benzo[d][1,2,3]triazole (14.08 g, 65 mmol) in DMF (12 mL) was added NaH (1.88 g, 78 mmol, 60% in oil), and the mixture was stirred at 25 ° C for 0.5 hours, then Mel (10.2 g, 71.7 mmol) was added, and the reaction mixture was stirred at the same temperature for 12 hours. The resulting mixture was concentrated under vacuum. The residue was purified using silica gel column chromatography (Hex: EtOAc = 3: 1) to give 6-bromo-4-fluoro-2-methyl-2H-benzo[d][1,2,3]triazole (3 g, 20% yield) as a yellow solid.

[0570] Step b: To a solution of 6-bromo-4-fluoro-2-methyl-2H-benzo[d][1,2,3]triazole (3 g, 13 mmol) in dioxane (50 mL) was added bis(pinacolato)diboron (6.6 g, 26 mmol) and potassium acetate (2.55 g, 26 mmol). The reaction mixture was degassed and backfilled with argon, and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane (0.265 g, 0.32 mmol) was added. The reaction mixture was stirred at 100°C for 10 hours. The resulting mixture was partitioned between EtOAc and water, the organic layer was concentrated under reduced pressure, and purified on a silica gel column with an eluent (Hex:EtOAc=7:3) to give 1.6 g of 4-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[d][1,2,3]triazole. 1H NMR (400 MHz, DMSO-d 6 )δ8.05(s,1H),7.29(d,J=11.1Hz,1H),4.56(s,3H),1.33(s,12H). M+=277

[0571] Intermediate 7

[0572]

[0573] Step a: 5-bromo-3-fluoropyridin-2-amine (28 g, 146.6 mmol) was dissolved in toluene (300 mL) and 1,1-dimethoxy-N,N-dimethylethylamine (35 mL, 234.5 mmol) was added. The reaction mixture was stirred under reflux overnight. Afterwards, the solvent was evaporated to obtain 35 g of N'-(5-bromo-3-fluoropyridin-2-yl)-N,N-dimethylacetamidine, which was used in the next step without further purification.

[0574] Step b: Dissolve the crude N'-(5-bromo-3-fluoropyridin-2-yl)-N,N-dimethylacetamidine (35 g, 134.5 mmol) in MeOH (300 mL) and add hydroxylamine hydrochloride (1.4 g, 161.5 mmol). Stir the reaction mixture at RT overnight. Afterwards, filter out the solid to give N-(5-bromo-3-fluoropyridin-2-yl)-N'-hydroxyacetamidine (15 g, 41% yield).

[0575] Step c: N-(5-bromo-3-fluoropyridin-2-yl)-N'-hydroxyacetamidine (15 g, 60.5 mmol) was dissolved in THF (200 mL). The solution was cooled and 2,2,2-trifluoroacetic anhydride (17.1 mL, 120.9 mmol) was added dropwise. The reaction mixture was stirred overnight at RT. Then, the solvent was evaporated in vacuo. The residue was dissolved in DCM / water and washed with NaHCO 3 Neutralize to pH = 8-9. Wash the organic layer with brine and 2 SO 4 Drying and evaporation under reduced pressure gave 6-bromo-8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (7 g, 50% yield).

[0576] Step d: 6-Bromo-8-fluoro-2-methyl-[1,2,4]triazolo[1,5-a]pyridine (17) (7 g, 30.4 mmol), bis(pinacolato)diboron (8.1 g, 32 mmol) and potassium acetate (6 g, 60.8 mmol) were mixed in dioxane (50 mL). The resulting mixture was evacuated and backfilled with argon (three cycles), and then Pd(dppf)2Cl2·DCM (0.53 g, 1.52 mmol) was added under argon atmosphere. The reaction mixture was stirred at 90°C for 18 hours under argon atmosphere, then cooled and filtered through SiO 2 The solid was dissolved in MTBE, stirred for 30 minutes and filtered to give 8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridine (5.5 g, 65% yield). 1 H NMR (400 MHz, DMSO-d 6 )δ8.74(s,1H),7.48(d,J=10.3Hz,1H),2.54(s,3H),1.33(s,12H). M+=277

[0577] Intermediate 8

[0578]

[0579] Step a: At 0°C, 4-methylbenzene-1-sulfonyl chloride (5 g, 26.2 mmol) was added to a mixture of 5-bromo-3-fluoropyridin-2-amine (5 g, 26.2 mmol) and pyridine (2.1 g, 26.2 mmol, 2.1 mL), and the reaction mixture was stirred for 12 hours at 100°C under a nitrogen atmosphere. The mixture was concentrated, then water (300 mL) was added, and extracted and concentrated with EtOAc (200 mL×2) to give N-(5-bromo-3-fluoropyridin-2-yl)-4-methylbenzenesulfonamide (6.9 g, 19 mmol) as an off-white solid. MS: m / z 347.0 [M+2H] +

[0580] Step b: To a solution of N-(5-bromo-3-fluoro-2-pyridinyl)-4-methyl-benzenesulfonamide (20 g, 57.94 mmol) and 2-iodoacetamide (10.72 g, 57.94 mmol) in DMF (100 mL) was added DIPEA (14.98 g, 115.88 mmol, 20.2 mL). The reaction mixture was stirred at 80 ° C for 16 hours. The mixture was concentrated and the crude material was purified by silica column chromatography (DCM / MeOH=10 / 1 to 6 / 1) to give 2-[(2E)-5-bromo-3-fluoro-2-(p-toluenesulfonylimino)-1-pyridinyl]acetamide (6.5 g, 28% yield) as a white solid.

[0581] Step c: To a solution of 2-[(2E)-5-bromo-3-fluoro-2-(tosylimino)-1-pyridinyl]acetamide (6 g, 14.92 mmol) in DCM (80 mL) was added (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (18.80 g, 89.50 mmol, 12.4 mL) at 0 °C. 2 The reaction mixture was stirred at 25° C. for 12 hours under atmosphere. The mixture was concentrated and the crude material was purified by silica column chromatography (DCM / MeOH=20 / 1 to 10 / 1) to give N-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide (3 g, 61% yield) as an off-white solid.

[0582] Step d: To a solution of N-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide (3.2 g, 9.81 mmol) in THF (30 mL) and water (6 mL) was added NaOH (1.18 g, 29.44 mmol) at 20 °C. 2 The reaction mixture was stirred at 60°C for 12 hours under a 37°C atmosphere. The mixture was concentrated. The residue was diluted with water (30 mL) and extracted with DCM (60 mL x 3). The organic layer was washed with brine (100 mL) and purified by Na 2 SO 4 Drying, filtration and concentration gave 6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-amine (2.0 g, 88% yield) as a light yellow solid. MS: m / z 229.8 [M+H] +

[0583] Intermediate 9

[0584]

[0585] Step a: To a stirred solution of methyl 2-amino-3-methylbenzoate (48 g, 290.6 mmol) in acetonitrile (500 mL) was added N-bromosuccinimide (52 g, 290.6 mmol) in portions at room temperature. The resulting mixture was stirred overnight at RT. Acetonitrile was evaporated under reduced pressure. The residue was diluted with water (500 mL) and the product was extracted with DCM (3×200 mL). The combined organic layers were washed with water (3×150 mL) and purified by Na 2 SO 4 Drying, filtration and evaporation under reduced pressure gave 67 g (yield 95%) of methyl 5-bromo-2-methyl-2H-indazole-7-carboxylate.

[0586] Step b: To a stirred solution of methyl 2-amino-5-bromo-3-methylbenzoate (65 g, 266.3 mmol) in AcOH (3000 mL) was added an aqueous solution of sodium nitrite (21 g, 306.2 mmol). The resulting mixture was stirred overnight. The formed precipitate was filtered out. The mother liquor was concentrated under reduced pressure. The residue was diluted with water (400 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with water (3×150 mL) and purified by Na 2 SO 4 Drying, filtration and evaporation under reduced pressure gave 34 g (yield 50%) of methyl 5-bromo-2H-indazole-7-carboxylate.

[0587] Step c: To a stirred solution of 5-bromo-2-methyl-2H-indazole-7-carboxylic acid methyl ester (25 g, 98 mmol) in DCM (300 mL) was added triethyloxonium tetrafluoroborate (18.1 g, 122.5 mmol) in portions at 0°C. The reaction mixture was stirred at RT for 3 days. The resulting mixture was washed with water (3×100 mL). The organic layer was purified by Na 2 SO 4 Drying, filtration and evaporation in vacuo afforded 19 g (73% yield) of methyl 5-bromo-2-methyl-2H-indazole-7-carboxylate.

[0588] Step d: To a stirred solution of methyl 5-bromo-2H-indazole-7-carboxylate (10 g, 37.2 mmol) in THF was added an aqueous solution of KOH (2.7 g, 48.3 mmol). The reaction mixture was stirred for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water and precipitated with NaHSO 4Acidify to slightly acidic pH, filter the precipitate, dry to obtain 9 g of the corresponding acid, which is dissolved in THF and 1,1'-carbonyldiimidazole (8.6 g, 55.7 mmol) is added in portions. The resulting mixture is stirred for 4 hours. Ammonia is then bubbled through the reaction mixture for 15 minutes. The resulting mixture is concentrated in vacuo. The solid residue is washed several times with water and dried to obtain 8.4 g of 5-bromo-2-methyl-2H-indazole-7-carboxamide.

[0589] Step e: To a stirred mixture of 5-bromo-2-methyl-2H-indazole-7-carboxamide (8.4 g, 33 mmol) and pyridine (13 g, 165.3 mmol) in DCM (100 mL) was added TFAA (10.4 g, 49.5 mmol) dropwise. The resulting mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (100 mL) and washed with water (3×50 mL). The organic layer was purified by Na 2 SO 4 Drying, filtration and evaporation in vacuo afforded 7.7 g (98% yield) of 5-bromo-2-methyl-2H-indazole-7-carbonitrile.

[0590] Step f: 5-Bromo-2-methyl-2H-indazole-7-carbonitrile (8) (7.8 g, 33 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (9.2 g, 36.3 mmol) and potassium acetate (6.5 g, 66 mmol) were mixed in dioxane (80 mL). The resulting mixture was evacuated and backfilled with argon (three cycles), and then Pd(dppf)Cl was added under argon atmosphere. 2 DCM (0.78 g, 3.3 mmol). The reaction mixture was stirred at 90 °C for 15 h under argon atmosphere, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2 x 20 mL) and discarded. The obtained mixture was concentrated under reduced pressure. The residue was dissolved in MTBE and filtered through SiO 2 The product was filtered through a short pad of Celite®. MTBE was evaporated under reduced pressure. The residue was crystallized from MTBE / hexane to give 3.2 g of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole-7-carbonitrile. 1 H NMR (400 MHz, DMSO-d 6 )δ8.68(s,1H),8.48(s,1H),7.91(s,1H),4.26(s,3H),1.32(s,12H).

[0591] M+1=283

[0592] Intermediate 10

[0593]

[0594] Step a: At 0 ° C, hydrazine (48.33 g, 1.51 mol, 48.33 mL) was added to a stirred solution of 4-bromo-2,6-difluorobenzaldehyde (50.0 g, 226.25 mmol, 226.25 mL) in THF (700 mL). The resulting mixture was warmed to 25 ° C and stirred at the same temperature for 16 hours. The solvent was removed under reduced pressure. The residual solid was dissolved in DMSO (600 mL), and triethylamine (45.79 g, 452.49 mmol, 63.07 mL) was then added, and the reaction mixture was stirred at 80 ° C for 18 hours. The obtained mixture was poured into water (1000 mL) and extracted with EtOAc (700 mL), the organic phase was separated, and the reaction mixture was purified by Na 2 SO 4 Drying and evaporation to dryness gave 6-bromo-4-fluoro-1H-indazole.

[0595] Step b: To a mixture of 6-bromo-4-fluoro-1H-indazole (40.0 g, 186.03 mmol) in THF (700 mL) at 20°C, potassium tert-butoxide (31.31 g, 279.04 mmol) was added. The mixture was stirred at 20°C for 30 minutes, and then iodomethane (39.61 g, 279.04 mmol, 17.37 mL, 1.5 equivalents) was added over 30 minutes. The mixture was stirred at 60°C overnight. Take a certain amount of sample and 1 The reaction mixture was then poured into water (1000 mL), extracted with EtOAc (1000 mL), and the organic phase was purified by Na 2 SO 4 Drying and evaporation to dryness gave 56 g of a yellow solid. The product was purified by FC ( Interchim; 330g SiO 2 , Hex / EtOAc, where EtOAc is 0-95%, flow rate = 120 mL / min, R f =5CV) to afford 6-bromo-4-fluoro-1-methyl-1H-indazole (20.0 g, 44% yield) as a yellow solid.

[0596] Step c: Potassium acetate (4.28 g, 43.66 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (6.1 g, 24.01 mmol) were added to a solution of 6-bromo-4-fluoro-1-methyl-1H-indazole (5.0 g, 21.83 mmol) in anhydrous dioxane (700 mL). The solution was degassed with argon for 30 minutes. Then, d(dppf)Cl was added. 2 ·CH 2 Cl 2 (1.78 g, 2.18 mmol), and the resulting solution was stirred under reflux for 12 hours. 1 The reaction mixture was then evaporated to dryness, poured into water (350 mL), extracted with EtOAc (450 mL), and the organic phase was purified by Na 2 SO 4 Dry and evaporate to dryness. The product is purified by FC ( Interchim; 120g SiO 2 , Hex / EtOAc, wherein EtOAc is 0-95%, flow rate = 120 mL / min) to give 4-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.02 g, yield 10%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d 6 )δ8.54(s,1H),7.78(s,1H),6.86(d,J=10.9Hz,1H),4.20(s,3H),1.30(s,12H). M+=277

[0597] Intermediate 11

[0598]

[0599] Step a: Under argon atmosphere, add the previously prepared LiAlH 4 To a suspension of 5-bromo-2-methyl-2H-indazole-7-carboxylic acid methyl ester (0.68 g, 17.8 mmol) in THF (50 mL) was added dropwise a solution of 5-bromo-2-methyl-2H-indazole-7-carboxylic acid methyl ester (4 g, 14.9 mmol). The resulting mixture was stirred at RT for 1.5 hours, then water (5 mL) as a 20% solution in THF was added dropwise. The reaction mixture was filtered, and the mother liquor was concentrated under reduced pressure to give 2.6 g of 5-bromo-2-methyl-2H-indazole-7-yl)methanol.

[0600] Step b: To a stirred solution of 5-bromo-2-methyl-2H-indazol-7-yl)methanol (2.6 g, 10.8 mmol) in THF (50 mL) was added MnO 2 (4.7 g, 53.9 mmol). The resulting mixture was stirred at 70°C for 2 days. The reaction mixture was filtered; the mother liquor was concentrated in vacuo to give 2.2 g of 5-bromo-2-methyl-2H-indazole-7-carbaldehyde.

[0601] Step c: To a stirred solution of 5-bromo-2-methyl-2H-indazole-7-carbaldehyde (2.2 g, 9.2 mmol) in DCM (40 mL) was added diethylaminosulfur trifluoride (DAST, 5 g, 27.6 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was washed with Na 2 CO 3 The solution was quenched. The organic layer was washed with water (2×30 mL) and 2 SO 4 Drying, filtration and evaporation in vacuo gave 2.5 g of 5-bromo-7-(difluoromethyl)-2-methyl-2H-indazole.

[0602] Step d: 5-Bromo-7-(difluoromethyl)-2-methyl-2H-indazole (2.5 g, 9.6 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (2.67 g, 10.5 mmol) and potassium acetate (1.88 g, 19.2 mmol) were mixed in dioxane (40 mL). The resulting mixture was evacuated and backfilled with argon (three cycles), and then Pd(dppf)Cl was added under argon atmosphere. 2 DCM (0.25 g, 9.6 mmol). The reaction mixture was stirred at 90 °C for 15 h under argon atmosphere, then cooled and filtered. The filter cake was washed with 1,4-dioxane (2 x 20 mL) and discarded. The obtained mixture was concentrated under reduced pressure. The residue was dissolved in MTBE and filtered through SiO 2 The product was filtered through a short pad of Celite®. MTBE was evaporated under reduced pressure. The residue was crystallized from MTBE / hexane to give 1.17 g of 7-(difluoromethyl)-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole. 1 H NMR (400 MHz, chloroform-d) δ 8.34 (s, 1H), 8.02 (s, 1H), 7.89 (s, 1H), 7.32–6.98 (m, 2H), 4.29 (s, 3H), 1.38 (s, 12H). M+ = 227

[0603] Intermediate 12

[0604]

[0605] Step a: To a solution of 5-bromo-3-fluoropyridin-2-amine (5 g, 26 mmol) in DCM (50 mL) cooled with an ice bath was added dropwise a solution of (O-(mesitylsulfonyl)hydroxylamine) (6.2 g, 29 mmol) in DCM (100 mL). The reaction mixture was stirred overnight at RT. The precipitated solid was collected and dried to give 6.2 g of the crude desired compound (yield 58%), which was used as is.

[0606] Step b: To a solution of the salt obtained in the previous step (6.2 g, 15 mmol) and KOH (1.28 g, 23 mmol) in methanol (100 mL) was added tert-butyl 4-formylpiperidine-1-carboxylate (3.2 g, 15 mmol), and the reaction mixture was stirred at RT overnight. The resulting mixture was evaporated under reduced pressure, the residue was diluted with EtOAc, and washed with water and brine. The organic layer was purified by Na 2 SO 4 Drying and evaporation under reduced pressure gave 3.8 g of tert-butyl 4-(6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)piperidine-1-carboxylate (yield 62%), which was used crude. 1H NMR (400 MHz, DMSO-d6) δ 9.25 (d, J = 1.5 Hz, 1H), 7.95 (dd, J = 9.9, 1.6 Hz, 1H), 3.96 (d, J = 13.1 Hz, 2H), 3.11 (tt, J = 11.6, 4.0 Hz, 1H), 2.96 (bs, 2H), 2.01 (dd, J = 13.7, 3.7 Hz, 2H), 1.73-1.58 (m, 2H), 1.41 (s, 9H). LCMS: 1.47 min, 298.2 [M–tBu] +

[0607] Intermediate 13

[0608]

[0609] Step a: To a solution of 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (50 mg, 229.78 μmol, 1.0 eq.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (70.02 mg, 275.73 μmol, 1.2 eq.) in dioxane (3 mL, 0.077 M) was added cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (16.81 mg, 22.98 μmol, 0.1 eq.) and KOAc (45.10 mg, 459.55 μmol, 2.0 eq.). The mixture was stirred at 90° C. under nitrogen for 2 hours. Then, the material was filtered, the filtrate was concentrated, and the concentrate was used directly in the next step without further purification. MS: m / z 365.1 [M+3MeO-2F] + ; RT: 1.78min (Method 10)

[0610] Intermediate 14

[0611]

[0612] To a solution of 5-bromo-3-fluoro-pyridin-2-amine (964 mg, 3.49 mmol) and (2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid (1 g, 5.24 mmol) in dioxane (12 mL) and water (4 mL) was added Cs 2 CO 3 (3.41 g, 10.47 mmol) and Pd(dppf)Cl 2 (255 mg, 0.35 mmol). The mixture was stirred at 90°C for 16 hours under nitrogen. The mixture was extracted with EtOAc (15 mL x 3) and washed with Na 2 SO 4 The product was dried. The combined organic phases were filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0% to 100% EtOAc:PE) to give 3-fluoro-5-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)pyridin-2-amine (312 mg, 1.2 mmol, 34% yield) as a white fluffy solid. MS: m / z 261.1 [M+H] + , 1 HNMR (400MHz, DMSO-d6) δppm: 8.68 (s, 1H), 8.16 (s, 1H), 7.85-7.67 (m, 2H), 7.48 (d, J = 13.0Hz, 1H), 6.44 (s, 2H), 2.36 (s, 3H).

[0613] Section 3. Synthetic Methods for Preparing the Disclosed Compounds

[0614] Example 1 - Compound 64

[0615]

[0616] Step a:3- (2- bromoacetyl) azetidine -1- tert-butyl formate (455mg, 1.64mmol, 1.25eq.) and 5- bromo-3-fluoro-pyridine -2-amine (250mg, 1.31mmol, 1.0eq.) were dissolved in water (6.5mL, 0.2M) and then heated to 80 ° C for 16 hours. Then, the solution was concentrated, then dry loaded onto a normal phase silica column and purified by 0-100% EtOAc: heptane (7 minutes), followed by 0-25% MeOH: DCM (5 minutes). The product was eluted at 1% MeOH. 3- (6- bromo-8-fluoro-imidazo [1,2-a] pyridine -2-yl) azetidine -1- tert-butyl formate (227.5mg, 24% yield) was isolated. MS: m / z 313.9[M+H] + .

[0617] Step b: tert-Butyl 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)azetidine-1-carboxylate (56.9 mg, 78.38 μmol, 1.0 eq.) and 7-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (29.40 mg, 94.06 mmol, 1.2 eq.) were dissolved in water (1 mL, 0.078 M) and dioxane (1 mL, 0.078 M), and then cesium carbonate (51.08 mg, 156.7 μmol, 2 eq.) and Pd(dppf) were added. 2 Cl DCM adduct (6.40 mg, 7.84 μmol, 0.1 eq.). The solution was then degassed with nitrogen and then heated to 100 °C for 16 hours. The solution was then concentrated and tert-butyl 3-(8-fluoro-6-(7-fluoro-2-methyl-2H-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl)azetidine-1-carboxylate was concentrated to a deprotected crude product. MS: m / z 440.2 [M+H] +

[0618] Step c: tert-Butyl 3-(8-fluoro-6-(7-fluoro-2-methyl-2H-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl)azetidine-1-carboxylate (34.44 mg, 78.38 μmol, 1.0 eq) was dissolved in DCM (1 mL, 0.078 M), followed by the addition of 4 M HCl in dioxane (196 μL, 10 eq.). The solution was then stirred at 40 °C for 16 hours, then concentrated and subjected to HPLC purification (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H 2 O; modifier: 0.1% TFA), to obtain 5-(2-(azetidin-3-yl)-8-fluoroimidazo[1,2-a]pyridin-6-yl)-7-fluoro-2-methyl-2H-indazole (2.5 mg, 7.05%). MS: m / z 340.2 [M+H] +; RT: 0.99 min (method 4); NMR: 1 H NMR(600MHz,DMSO-d6)δppm 4.21-4.34(m,9H)7.45-7.51(m,1H)7.70-7.75(m,1H)7.91-7.95(m,1H)7.98-8.02(m,1H)8.54-8.58(m,1H)8.88-8.91(m,1H).

[0619] Using the procedure described in Example 1 above, other compounds described herein are prepared by substituting the appropriate bromoketone starting material in step a, the appropriate boronate ester or acid equivalent in step b, suitable reagents and reaction conditions to obtain, for example, a compound selected from the following:

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626] Example 2 - Compound 66

[0627]

[0628] Step a: To a solution of tert-butyl 4-(2-bromoacetyl)-2-azabicyclo[2.1.1]hexane-2-carboxylate (70 mg, 230 μmol) in t-BuOH (5 mL) was added 3-fluoro-5-(7-fluoro-2-methyl-indazol-5-yl)pyridin-2-amine (50 mg, 192 μmol) and NaHCO 3 (32 mg, 384 μmol), and the mixture was stirred at 70 ° C for 16 hours. The mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (PE / EA = 1 / 1) to give 4-[8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl]-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (50 mg, yield 56%) as a yellow solid. MS: m / z 466.6 [M+H] +

[0629] Step b: 4-[8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl]-2-azabicyclo[2.1.1]hexane-2-carboxylic acid tert-butyl ester (50 mg, 107 μmol) was dissolved in 4M HCl in EtOAc (20 mL), and the mixture was stirred at 25°C for 1 hour. The mixture was concentrated in vacuo and purified by preparative HPLC (Boston Prime C18 150*30mm*5um; water NH 3 H 2 O+NH 4 HCO 3 )-ACN) to give 2-(2-azabicyclo[2.1.1]hexan-4-yl)-8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridine (4.1 mg, yield 10%). MS: m / z 366.2[M+H] +

[0630] Step c: To a solution of 2-(2-azabicyclo[2.1.1]hex-4-yl)-8-fluoro-6-(7-fluoro-2-methyl-indazole-5-yl)imidazo[1,2-a]pyridine (30 mg, 82.1 μmol) in 1,2-dichloroethane (0.4 mL) and EtOH (2 mL) was added paraformaldehyde (98.5 mg, 82.1 μmol, 112 μL) and TEA (164 μmol, 23 μL), and the mixture was stirred at 25 ° C for 10 minutes. Then, sodium triacetoxyborohydride (35 mg, 164 μmol) was added, and the mixture was stirred at 25 ° C for 0.5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (Boston PrimeC18 150*30mm*5um; water NH 3 H 2 O+NH 4 HCO 3 )-ACN) to give 7-fluoro-5-[8-fluoro-2-(2-methyl-2-azabicyclo[2.1.1]hexan-4-yl)imidazo[1,2-a]pyridin-6-yl]-2-methyl-indazole (6.2 mg, yield 20%) as a white solid. MS: m / z 380.3 [M+H] + ; 1 H NMR (500MHz, methanol-d4) δppm=8.59(d,J=1.37Hz,1H),8.38(d,J=2.59Hz,1H),7.89(d,J=2.90Hz,1H),7.82(d,J=1.22Hz,1H),7.52(dd,J=12.0 5,1.37Hz,1H),7.37(dd,J=12.66,1.37Hz,1H),4.26(s,3H),3.66(s,1H),3.27-3.14(m,2H),2.69(s,3H),2.28(s,2H),2.08-1.99(m,2H).

[0631] Using the procedure described in Example 2 above, other compounds described herein are prepared by substituting the appropriate bromoketone and aminopyridine starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0632]

[0633] Example 3 - Compound 79

[0634]

[0635] Step a: To a solution of tert-butyl N-[1-(2-bromoacetyl)-2-oxabicyclo[2.1.1]hexan-4-yl]carbamate (92.3 mg, 288.2 μmol) in t-BuOH (5 mL) was added 3-fluoro-5-(7-fluoro-2-methyl-indazol-5-yl)pyridin-2-amine (50 mg, 192.1 μmol) and NaHCO 3 (48.4 mg, 576.39 μmol), and the mixture was stirred at 70° C. for 16 hours. The crude material was purified by flash silica gel chromatography (Combi-Flash (PE / EA=3 / 1 to 1 / 5). MS: m / z 482.1 [M+H] +

[0636] Step b: At 0 ° C, NaH (16.6 mg, 415.3 μmol, purity 60%) was added to a solution of tert-butyl N-[1-[8-fluoro-6-(7-fluoro-2-methyl-indazole-5-yl)imidazo[1,2-a]pyridin-2-yl]-2-oxabicyclo[2.1.1]hexan-4-yl]carbamate (100 mg, 207.6 μmol) in THF (5 mL) and stirred for 0.5 hours. Then, iodomethane (415.3 μmol, 26 μL) was added, and the mixture was stirred at 20 ° C for 2 hours. The mixture was concentrated and then water (80 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo to give N-[1-[8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl]-2-oxabicyclo[2.1.1]hex-4-yl]-N-methyl-carbamic acid tert-butyl ester (30 mg), which was used in the next step in crude form. MS: m / z 496.1 [M+H] + .

[0637] Step c: At RT, a solution of N-[1-[8-fluoro-6-(7-fluoro-2-methyl-indazole-5-yl)imidazo[1,2-a]pyridin-2-yl]-2-oxabicyclo[2.1.1]hex-4-yl]-N-methyl-carbamic acid tert-butyl ester (30 mg, 60.54 μmol) in TFA (1 mL) and DCM (3 mL) was stirred for 3 hours. The mixture was concentrated in vacuo and purified by preparative HPLC (Boston Prime C18 150*30mm*5um; water NH 3 H 2 O+NH 4 HCO 3)-ACN) to give 1-[8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridin-2-yl]-N-methyl-2-oxabicyclo[2.1.1]hexan-4-amine (2.7 mg, 11%). MS: m / z 396.3[M+H] + ; 1 H NMR (400MHz, methanol-d4) δppm=8.62(d,J=1.31Hz,1H),8.37(d,J=2.62Hz,1H),7.97(d,J=2.98Hz,1H),7.82(d,J=1.07Hz,1H),7.52(dd, J=12.10,1.25Hz,1H),7.37(dd,J=12.64,1.19Hz,1H),4.26(s,3H),3.80(s,2H),2.52(s,3H),2.41-2.33(m,2H),2.06-1.95(m,2H).

[0638] Using the procedure described in Example 3 above, other compounds described herein are prepared by substituting the appropriate bromoketone and aminopyridine starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0639]

[0640] Example 4 - Compound 161 and / or 185

[0641]

[0642] Step a: To a solution of (1S,5R)-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-6-carboxylic acid (600 mg, 2.64 mmol) in DCM (4 mL) was added (COCl) at 0 °C. 2 4-(1S, 5R)-6-(2-bromoacetyl)-3-azabicyclo [3.1.0] hexane-3-tert-butyl formate (600mg, crude product) was added to 4-(1S, 5R)-6-(2-bromoacetyl)-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (600mg, crude product) in vacuo.

[0643] Step b: To a solution of (1S,5R)-6-(2-bromoacetyl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (300 mg, 986.26 μmol) and 5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-fluoro-pyridin-2-amine (100 mg, 388.70 μmol) in t-BuOH (4 mL) was added NaHCO 3 (165.71 mg, 1.97 mmol, 76.72 μL). The reaction was stirred at 80 ° C for 16 hours. The mixture was filtered and concentrated, and the residue was purified by preparative HPLC. (1S, 5R)-6-[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (60 mg, 125.55 μmol, yield 12.7%, purity 96.8%) was obtained as a yellow oil. MS: m / z 463.3[M+H] + .

[0644] Step c: To a solution of (1S,5R)-6-[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (20 mg, 43.24 μmol) in EtOAc was added HCl in EtOAc (0.5 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was filtered and concentrated. The residue was purified by preparative HPLC. 6-[2-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]-8-fluoro-imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (10 mg, 24.83 μmol, yield 57.4%) was obtained as a white solid. MS: m / z 363.2 [M+H] + ; RT: 1.948min (Method 8); 1 H NMR: (400MHz, methanol-d 4 )δppm=8.99(s,1H),8.47(s,0.5H),7.93(s,1H),7.90(s,1H),7.80-7.70(m,1H),7.58(s ,1H),3.60-3.50(m,4H),2.67(s,3H),2.49(s,3H),2.40-2.30(m,2H),2.15-2.10(m,1H).

[0645] Step d: To a solution of 6-[2-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]-8-fluoro-imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (30 mg, 82.78 μmol) in EtOH (3 mL) was added paraformaldehyde (99.30 mg, 82.78 μmol, 112.84 μL), TEA (25.13 mg, 248.34 μmol, 34.61 μL) and DCE (16.38 mg, 165.56 μmol, 13.11 μL). The mixture was stirred at 25 ° C for 20 minutes. Sodium triacetoxyborohydride (35.09 mg, 165.56 μmol) was then added and the mixture was stirred at 25 ° C for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Boston Green ODS150*30mm*5um; conditions: water (FA)-ACN, starting B 3, ending B 33; gradient time (min): 12; 100% B holding time (min): 2; flow rate (ml / min): 25) to give 6-[8-fluoro-2-[(1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (4.7 mg, 12.5 μmol, yield 15.1%) as a yellow solid. MS: m / z 377.3[M+H] + ; RT: 0.628min (Method 10); 1 H NMR: (400MHz, methanol-d 4 )δppm=8.95(d,J=0.8,1H),8.51(s,1H),7.91(s,1H),7.86(s,1H),7.80-7.70(m,1H),7.56(s,1H),3.55-3. 50(m,3H),3.20-3.10(m,2H),2.71(s,3H),2.66(s,3H),2.48(s,3H),2.40-2.30(m,1H),2.20-2.10(m,2H).

[0646] Using the procedure described in Example 4 above, other compounds described herein are prepared by substituting the appropriate carboxylic acid starting material in step a and the aminopyridine intermediate in step b, suitable reagents and reaction conditions to obtain, for example, a compound selected from the following:

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653] Example 5 - Compound 1

[0654]

[0655] Step a: At 25°C, in N 2 Under the condition of 4-[8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylic acid tert-butyl ester (550 mg, 1.24 mmol), 6-chloro-2,8-dimethyl-imidazo[1,2-b]pyridazine (224.31 mg, 1.24 mmol) and K 2 CO 3 To a solution of (512 mg, 3.71 mmol) in dioxane (1 mL) and water (0.5 mL) was added Pd(dppf)Cl 2 (90.3mg, 123.5μmol). The mixture was stirred at 90 ° C for 2 hours. The mixture was filtered and concentrated to give a crude product. The crude product was purified by flash silica gel chromatography (from PE to EtOAc, 0-100%) to give 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylic acid tert-butyl ester (270mg, yield 47%) as a white solid. MS: m / z 465.2[M+H] +

[0656] Step b: To a solution of 4-[6-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylic acid tert-butyl ester (60 mg, 0.129 mmol) in DCM (5 mL) was added TFA (6.53 mmol, 0.5 mL) at 20° C. The mixture was stirred at 20° C. for 20 minutes. The mixture was concentrated to give a residue, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*25mm*5um; conditions: water (0.225% FA)-ACN; start B: 0; end B: 20; gradient time (min): 12; 100% B holding time (min): 2; flow rate (ml / min): 25) to give 6-(2,8-dimethylimidazo[1,2-a]pyridin-6-yl)-8-fluoro-2-(4-piperidinyl)imidazo[1,2-a]pyridine (43 mg, yield 91%) as an off-white solid. MS: m / z 365.1 [M+H] + ; 1 H NMR: (400 MHz, methanol-d4) δ ppm = 9.28 (s, 1H), 8.19-8.35 (m, 2H), 7.98-8.11 (m, 2H), 3.55 (br d, J = 12.8 Hz, 2H), 3.15-3.30 (m, 3H), 2.71-2.87 (m, 3H), 2.65 (s, 3H), 2.29-2.41 (m, 2H), 1.97-2.13 (m, 2H).

[0657] Using the procedure described in Example 5 above, other compounds described herein are prepared by substituting the appropriate boronic acid or ester equivalent starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666] Example 6 - Compound 153 and / or 166

[0667]

[0668] Step a: tert-Butyl 4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (885.3 mg, 1.93 mmol, 1.0 eq.) was dissolved in dioxane (11.11 mL, 0.174 M), followed by the addition of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (736.64 mg, 2.90 mmol, 1.5 eq.) and potassium acetate (379.59 mg, 3.87 mmol, 2 eq.). The solution was then purged with nitrogen, followed by the addition of Pd(dppf)Cl 2 CH 2 Cl 2 (78.96 mg, 96.69 μmol, 0.05 eq.). The solution was then stirred at 60 ° C for 4 hours, then warmed to 100 ° C and stirred for 16 hours. The solution was then concentrated in vacuo, and the crude product was then injected into the normal phase and purified by 0-25% MeOH: DCM. The product was eluted in 15% methanol for 12 minutes. The identified eluted portions were combined and concentrated to give [2-(1-tert-butoxycarbonyl-4-piperidinyl)-8-fluoro-imidazo[1,2-a]pyridin-6-yl]boronic acid (796.8 mg, 1.82 mmol, yield 94%). MS: m / z 308.0[M+H] + ; RT: 0.54min (Method 4).

[0669] Step b: 6-Chloro-8-(difluoromethyl)-2-methylimidazo[1,2-b]pyridazine (37.52 mg, 0.126 mmol, 1.1 eq.) was dissolved in dioxane (1.5 mL, 0.08 M) and water (0.25 mL, 0.46 M), followed by the addition of [2-(1-tert-butyloxycarbonyl-4-piperidinyl)-8-fluoro-imidazo[1,2-a]pyridin-6-yl]boronic acid (50 mg, 0.114 mmol, 1.0 eq.) and potassium carbonate (111.6 mg, 0.343 mmol, 3 eq.). The solution was then purged with nitrogen, followed by the addition of Pd(dppf)Cl 2 CH 2 Cl 2(11.1 mg, 17.14 μmol, 0.15 eq.). The solution was then stirred at 120 °C for 16 h, then concentrated and used as is. tert-Butyl 4-(6-(8-(difluoromethyl)-2-methylimidazo[1,2-b]pyridazin-6-yl)-8-fluoroimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate was obtained in an assumed quantitative yield (57.19 mg, 0.114 mmol, 72.3% yield) MS: m / z 501.2 [M+H] + RT: 0.66 min (Method 4).

[0670] Step c: tert-Butyl 4-(6-(8-(difluoromethyl)-2-methylimidazo[1,2-b]pyridazin-6-yl)-8-fluoroimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (57.19 mg, 0.114 mmol, 1.0 eq.) was dissolved in DCM (3 mL, 0.04 M) followed by the addition of 4M HCl in dioxane (285 μL, 1.14 mmol, 10.0 eq.). The solution was then stirred at 50° C. for 2 hours followed by the addition of an additional aliquot of 4M HCl in dioxane (285 μL, 0.114 mmol, 1.0 eq.). The solution was stirred at 50°C for another 16 hours, then concentrated and purified by preparative HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; modifier: 0.1% TFA). 8-(difluoromethyl)-6-(8-fluoro-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)-2-methylimidazo[1,2-b]pyridazine (5.4 mg, yield 9%) was obtained. MS: m / z 401.3 [M+H] + ; RT: 0.93 min (Method 3) 1H NMR (600 MHz, DMSO-d6) δ ppm 1.86-1.95 (m, 2H) 2.15-2.23 (m, 2H) 2.41-2.49 (m, 3H) 3.03-3.16 (m, 3H) 3.37-3.42 (m, 2H) 7.50-7.58 (m, 1H) 7.80-7.86 (m, 1H) 7.95-8.02 (m, 2H) 8.26-8.30 (m, 1H) 8.30-8.39 (m, 1H) 8.57-8.66 (m, 1H) 9.28-9.38 (m, 1H).

[0671] Step d: 8-(Difluoromethyl)-6-[8-fluoro-2-(4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]-2-methyl-imidazo[1,2-b]pyridazine (17.32 mg, 38.93 umol, 1.0 eq.) was dissolved in acetonitrile (203.31 uL, 0.2 M), followed by the addition of TEA (7.88 mg, 77.86 umol, 2.0 eq.). The solution was stirred for one minute, followed by the addition of paraformaldehyde (46.70 mg, 38.93 umol, 1.0 eq.) and acetic acid (11.69 mg, 194.66 umol, 5.0 eq.). The solution immediately fumed and was stirred at RT for 10 minutes, followed by the addition of sodium cyanoborohydride (4.89 mg, 77.86 umol, 2.0 eq.). The solution was then stirred for 30 minutes, then concentrated, then re-placed in DMSO and filtered, and the crude product was then injected into the reverse phase and purified by HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; modifier: 0.1% TFA). The identified eluted fractions were collected, combined and concentrated to obtain a transparent film. The material was then redissolved in a very small amount of ACN and water and then lyophilized to obtain 8-(difluoromethyl)-6-[8-fluoro-2-(1-methyl-4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]-2-methyl-imidazo[1,2-b]pyridazine (10 mg, yield 47.15%) as a fluffy yellow powder, which was registered as is. MS: m / z 415.2[M+H] + ; RT: 0.46 min (Method 4). 1H NMR (400 MHz, methanol-d4) δ ppm 2.00-2.13 (m, 2H) 2.33-2.42 (m, 2H) 2.55-2.58 (m, 3H) 2.93-2.98 (m, 3H) 3.15-3.26 (m, 3H) 3.63-3.70 (m, 2H) 7.19-7.48 (m, 1H) 7.92-8.00 (m, 2H) 8.07-8.11 (m, 1H) 8.18-8.22 (m, 1H) 9.18-9.21 (m, 1H)

[0672] Using the procedure described in Example 6 above, other compounds described herein are prepared by substituting the appropriate heteroaryl halide starting material, suitable reagents and reaction conditions in step b to obtain, for example, a compound selected from the following:

[0673]

[0674]

[0675] Example 7 - Compound 4

[0676]

[0677] 6-[8-Fluoro-2-(4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]-2-methyl-imidazo[1,2-b]pyridazine (29.85 mg, 67.13 μmol, 1.0 eq.) was dissolved in DCM (370 μL, 0.2 M), and then acetic acid (4 μL, 67.13 μmol, 1 eq.) was added, followed by paraformaldehyde (80.5 mg, 67.13 μmol, 1.0 eq.). The solution was then stirred for 5 minutes, followed by the addition of sodium cyanoborohydride (4.2 mg, 67.1 μmol, 1.0 eq.). The solution was then stirred at RT for 4 hours, then concentrated, then redissolved in DMSO, filtered, and subjected to HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H 2 O; modifier: 0.1% TFA). 6-[8-fluoro-2-(1-methyl-4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]-2-methyl-imidazo[1,2-b]pyridazine (8.8 mg, yield 27%) was obtained as a yellow solid. MS: m / z 365.3 [M+H] + RT: 0.70min (Method 4). 1H NMR(600MHz,DMSO-d6)δppm 1.88-1.97(m,2H)2.23-2.29(m,2H)2.49(q,J=1.65Hz,3H)2.82-2.88(m,3H)2.99-3.06(m,1H)3.08-3.18(m,2H)3.52- 3.60(m,2H)7.73-7.76(m,1H)7.77-7.81(m,1H)7.98-8.01(m,1H)8.10-8.13(m,1H)8.14-8.18(m,1H)9.19-9.23(m,1H)

[0678] Using the procedure described in Example 7 above, other compounds described herein are prepared by substituting appropriate starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0679]

[0680]

[0681]

[0682] Example 8 - Compound 69

[0683]

[0684] To a solution of 6-[8-fluoro-2-(4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (20 mg, 54.88 μmol) in EtOH (1 mL) and DCE (0.2 mL) was added cyclobutanone (5.7 mg, 82.3 μmol, 6 μL) and TEA (109.7 μmol, 15 μL), and the mixture was stirred at 25 ° C for 10 minutes. Then, sodium triacetoxyborohydride (23 mg, 109.7 μmol) was added, and the mixture was stirred at 25 ° C for 0.5 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (Boston Prime C18 150*30mm*5um; water NH 3 H 2 O+NH 4 HCO 3 )-ACN) to give 6-[2-(1-cyclobutyl-4-piperidinyl)-8-fluoro-imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (14.5 mg, yield 63%) as a white solid. MS: m / z 419.3 [M+H] + ;1H NMR (500MHz, methanol-d4) δppm=8.99(s,1H),7.92(s,1H),7.83(d,J=2.59Hz,1H),7.78(d,J=11.90Hz,1H),7.57(s,1H),3.02( d,J=11.60Hz,2H),2.88-2.76(m,2H),2.67(s,3H),2.48(s,3H),2.21-2.08(m,4H),2.04-1.90(m,4H),1.82-1.72(m,4H).

[0685] Using the procedure described in Example 8 above, other compounds described herein are prepared by substituting the appropriate amine and carbonyl starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0686]

[0687]

[0688]

[0689] Example 9 - Compound 46

[0690]

[0691] 6-[8-Fluoro-2-(4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (30 mg, 82.32 μmol), 1-bromo-2-methoxy-ethane (11.4 mg, 82.32 μmol, 8 μL) and Cs 2 CO 3 A solution of (53.6 mg, 164 μmol) in DMF (2 mL) was stirred at 80 °C for 2 hours. The mixture was filtered and concentrated to give a crude product. The crude product was purified by preparative HPLC (Boston Prime C18 150*30 mm*5 um, water (NH 3 H 2 O+NH 4 HCO 3 )-ACN as mobile phase, from 32% to 62%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-[8-fluoro-2-[1-(2-methoxyethyl)-4-piperidinyl]imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (14.7 mg, yield 42%) as a white solid. MS: m / z 423.2[M+H] + ; 1HNMR: (400MHz, methanol-d4) δppm=9.01-8.95(m,1H),7.92(s,1H),7.85-7.72(m,2H),7.56(s,1H),3.62-3.54(m,2H),3.362(s,3H) ,3.17-3.06(m,2H),2.83-2.75(m,1H),2.69-2.62(m,5H),2.48(s,3H),2.32-2.23(m,2H),2.20-2.09(m,2H),1.91-1.74(m,2H).

[0692] Using the procedure described in Example 9 above, other compounds described herein are prepared by substituting the appropriate alkyl halide starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0693]

[0694]

[0695] Example 10 - Compound 74

[0696]

[0697] A solution of 6-[8-fluoro-2-(4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (60 mg, 164.6 μmol), acetoacetate (164.65 μmol, 16 μL) and pyridine (164.65 μmol, 13 μL) in DCM (2 mL) was stirred at 25 °C for 16 hours. The mixture was concentrated in vacuo to give a crude product, which was purified by preparative HPLC (Boston Prime C18 150*30mm*5um, water (NH 3 H 2 O+NH 4 HCO 3 )-ACN as mobile phase, from 30% to 70%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 1-[4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-1-piperidinyl]ethanone (25 mg, yield 37%) as a white solid. MS: m / z 407.2[M+H] + ; 1 H NMR: (400MHz, methanol-d4) δppm = 9.00-8.99 (d, J = 1.4Hz, 1H), 7.92 (s, 1H), 7.87-7.76 (m, 2H), 7.58-7.57 (d, J = 10.8Hz, 1H), 4.67-4.60 (m, 1H), 4.09-4. 01(m,1H),3.37-3.32(m,1H),3.13-3.04(m,1H),2.89-2.79(m,1H),2.67 -2.66(d,J=0.8Hz,3H),2.48(s,3H),2.22-2.1(m,5H),1.83-1.63(m,2H).

[0698] Example 11 - Compound 120

[0699]

[0700] 6-[8-Fluoro-2-(4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (20 mg, 52.14 μmol, 1.0 eq.) was dissolved in DCM (260 μL, 0.2 M), followed by the addition of TEA (15.8 mg, 156.4 μmol, 3.0 eq.). Then, propionyl propionate (7.5 mg, 57.3 μmol, 1.1 eq.) was slowly added, and the solution was stirred at RT for 16 hours, then concentrated, dissolved in DMSO, filtered, and then subjected to HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H 2 O; modifier: 0.1% TFA). 1-[4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-1-piperidinyl]propan-1-one (7.2 mg, yield 26%) was obtained as a white powder. MS: m / z 421.3[M+H] + ; RT: 0.96min (Method 3) 1 H NMR(600MHz,DMSO-d6)δppm 0.99-1.04(m,3H)1.47-1.55(m,1H)1.60-1.68(m,1H)1.99-2.07(m,2H)2.33 -2.39(m,2H)2.44-2.47(m,3H)2.62-2.66(m,3H)2.70-2.77(m,1H)3.01-3.0 7(m,1H)3.14-3.19(m,1H)3.92-3.97(m,1H)4.44-4.50(m,1H)7.75-7.79(m, 1H)7.80-7.85(m,1H)7.95-7.98(m,1H)8.16-8.19(m,1H)9.20-9.22(m,1H).

[0701] Using the procedure described in Example 11 above, other compounds described herein are prepared by substituting the appropriate acid chloride starting material, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0702]

[0703] Example 12 - Compound 113

[0704]

[0705] To a solution of 6-[8-fluoro-2-(4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (50 mg, 137 μmol) in MeOH (1 mL) were added (1-ethoxycyclopropyloxy)-trimethyl-silane (36 mg, 206 μmol, 41 μL), TEA (137 μmol, 19 μL) and sodium cyanoborohydride (14 mg, 220 μmol), and the mixture was stirred for 20 minutes at 25° C. Then, acetic acid (412 μmol, 24 μL) was added, and the mixture was stirred at 60° C. for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (column: Boston Green ODS 150×30 mm×5 um; conditions: water (HCl)-ACN; gradient (organic %): 0-100%, optimized for each example; flow rate (mL / min) 25) to give 6-[2-(1-cyclopropyl-4-piperidinyl)-8-fluoro-imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (13 mg, 23%) as a white solid. MS: m / z 405.1 [M+H]+; RT: 1.31 min.

[0706] Using the procedure described in Example 12 above, other compounds described herein are prepared by substituting appropriate starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0707]

[0708]

[0709] Example 13 - Compound 129

[0710]

[0711] Step a: In N 2 6-Bromo-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1 g, 3.48 mmol), 7-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (1.20 g, 3.83 mmol, hydrochloride), Pd(dppf)Cl 2 A mixture of DCM (284.46 mg, 348.3 μmol), dicesium carbonate (3.40 g, 10.45 mmol) in dioxane (9.3 mL) and water (2.3 mL) was stirred for 4 h. After cooling to RT, the mixture was washed with celite and MgSO 4Filtration (DCM / EtOAc eluent), concentration and purification by silica gel chromatography (24 g, 0-100% 3:1 EtOAc:EtOH in heptane, 10 min) gave 8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (250 mg, 20% yield). MS: m / z 357.1 [M+H] +

[0712] Step b: A mixture of 8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (250 mg, 701.6 μmol) and lithium hydroxide hydrate (58.88 mg, 1.40 mmol) in methanol (467 μL), THF (3.4 mL) and water (841 μL) was stirred at RT for 4 hours, neutralized with 4N HCl in dioxane at RT with stirring, concentrated under reduced pressure, and dried under high vacuum to obtain 8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridine-2-carboxylic acid, which was used crude in the next reaction (assumed yield 100%). MS: m / z 329.0 [M+H] +

[0713] Step c: T3P (274.1 μmol, 163 μL, 50% purity in ethyl acetate) and NEt 3 (365.55 μmol, 51 μL) was added to a solution of 8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)imidazo[1,2-a]pyridine-2-carboxylic acid (30 mg, 91 μmol) and N,1-dimethylpiperidin-4-amine (23.4 mg, 182.7 μmol) in THF (1.1 mL). Then, the ice bath was removed and the mixture was stirred at RT overnight. The mixture was quenched with water, extracted with EtOAc, and purified by MgSO 4 Dry, filter, concentrate, and perform HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H 2 O; modifier: 0.1% TFA) to give 8-fluoro-6-(7-fluoro-2-methyl-indazol-5-yl)-N-methyl-N-(1-methyl-4-piperidinyl)imidazo[1,2-a]pyridine-2-carboxamide (3.8 mg, yield 7%). MS: m / z 349.2 [M+H] + ; RT: 0.50min (method 4)

[0714] Using the procedure described in Example 17 above, other compounds described herein are prepared by substituting the appropriate boronate starting material, suitable reagents and reaction conditions in step b to obtain, for example, a compound selected from the following:

[0715]

[0716] Example 14 - Compounds 355 and 362

[0717]

[0718] Step a: To a solution of tert-butyl 4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (1.36 g, 3.83 mmol) in DMF (10 mL) was added K 2 CO 3 (1.59 g, 11.49 mmol) and 5-bromo-7-fluoro-2H-indazole (823 mg, 3.83 mmol). The mixture was stirred at 100 °C for 12 hours. Then, the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain a crude residue. The crude product was purified by flash silica gel chromatography (from PE / EtOAc=10 / 1 to 5 / 1) to obtain the product. Compound 4-(5-bromo-7-fluoro-indazol-2-yl)piperidine-1-carboxylic acid tert-butyl ester (492 mg, 1.24 mmol, yield 32.26%) was obtained as a yellow oil. MS: m / z 342.0 [M+H] + ; RT: 0.52min (method 3)

[0719] Step b: To a mixture of tert-butyl 4-(5-bromo-7-fluoro-2H-indazol-2-yl)piperidine-1-carboxylate (5 g, 12.6 mmol) in dioxane (120 mL) was added bis(pinacol)diboron (3.83 g, 15.1 mmol), KOAc (2.46 g, 25.1 mmol) and Pd(dppf)Cl2 (459.3 mg, 627.7 umol) at 25°C. The mixture was stirred at 120°C for 16 hours under a nitrogen atmosphere. The mixture was concentrated and then water (150 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4Dry, filter and concentrate. Then, the crude material was purified by flash chromatography (PE / EtOAc=5 / 1 to 2 / 1) to give tert-butyl 4-(7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl)piperidine-1-carboxylate (4.85 g, 10.9 mmol, 87% yield) as a white solid. MS: m / z 446.3 [M+H] + ; RT: 0.748min (method 3)

[0720] Step c: 4-[7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester (50 mg, 112 umol) was added to dioxane / H 2 O (5 mL) were added with 5-chloro-2,7-dimethyl-pyrazolo[1,5-a]pyrimidine (20 mg, 112.28 umol), K 2 CO 3 (46 mg, 336.8 umol) and PdCl 2 (dppf) (8 mg, 11.23 umol). The reaction mixture was stirred at 90 ° C for 2 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (from PE / EtOAc = 5 / 1 to 1 / 3) to give the product. 4- [5- (2,7-dimethylpyrazolo [1,5-a] pyrimidin-5-yl) -7-fluoro-indazole-2-yl] piperidine-1-carboxylic acid tert-butyl ester (30 mg, 59.22 umol) was obtained as a yellow solid. MS: m / z 465.3 [M + H] + ; RT: 0.468min (method 3)

[0721] Step d: 4-[5-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-7-fluoro-indazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester (78 mg, 168 umol) was dissolved in MeOH (4 mL) and treated with 4N HCl in dioxane (292 uL) and stirred at room temperature for 24 hours. The reaction was concentrated and used crude in the next step. MS: m / z 365.1 [M+H] + ; RT: 0.45min (Method 4)

[0722] Step e: 6-(7-fluoro-2-(piperidin-4-yl)-2H-indazol-5-yl)-2,8-dimethylimidazo[1,2-b]pyridazine (40 mg, 109.8 umol) was dissolved in THF (1 mL) with paraformaldehyde (131 mg, 109 umol, 149 uL), acetic acid (66 mg, 1.1 mmol, 63 uL), sodium cyanoborohydride (21 mg, 329 umol) and stirred overnight at 70 ° C. The resultant was diluted with water, extracted with EtOAc and dried over sodium sulfate, and purified by FCC using a 0-100% EtOAc-heptane gradient to give the title compound (41.5 mg, 36 umol). MS: m / z 379.1 [M+H] + ; RT: 1.63min (method 3)

[0723] Using the procedure described in Example 17 above, other compounds described herein are prepared by substituting the appropriate boronate starting material, suitable reagents and reaction conditions in step b to obtain, for example, a compound selected from the following:

[0724]

[0725]

[0726] Example 15 - Compound 135

[0727]

[0728] Step a: 6-bromo-4-fluoro-2H-indazole (1 g, 4.65 mmol) was dissolved in DMF (10 mL). Potassium carbonate (6.4 g, 46.5 mmol), tert-butyl 4-iodopiperidine-1-carboxylate (1.45 g, 4.65 mmol) were added and heated to 100 ° C overnight. The resultant was diluted with water and EtOAc, extracted with EtOAc, and the crude product was purified by silica column chromatography using a 0-100% EtOAc-heptane gradient to give tert-butyl 4-(6-bromo-4-fluoro-2H-indazole-2-yl)piperidine-1-carboxylate (60 mg, 3% yield) MS: m / z 341.8 [M-tBu+H] +

[0729] Step b: tert-butyl 4-(6-bromo-4-fluoro-indazol-2-yl)piperidine-1-carboxylate (30 mg, 75 μmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (21 mg, 75 μmol), PdCl2(dippf) (45 mg, 7.5 μmol) and Cs 2 CO3 A mixture of (49 mg, 151 μmol) in dioxane (3 mL) and water (847 μL) was treated with N 2 Degas, then heat in microwave at 100°C for 1 hour. The resultant was diluted with water and EtOAc, the phases separated and concentrated to give tert-butyl 4-(6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2H-indazol-2-yl)piperidine-1-carboxylate, used crude (assumed 100% yield). MS: m / z 465.1 [M+H] +

[0730] Step c: tert-Butyl 4-(6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-4-fluoro-2H-indazol-2-yl)piperidine-1-carboxylate (30 mg, 75 μmol) was dissolved in DCM (1 mL) and treated with TFA (0.5 mL) and stirred at room temperature for 2 hours. The reaction was concentrated and purified by reverse phase HPLC using Waters XSelect CSH Prep C18 5um OBD 30×100mm and 5-65% ACN-water gradient using TFA modifier (2.8 mg, yield 10%). MS: m / z 365.1 [M+H] + ; RT 1.01min (Method 3)

[0731] Example 16 - Compounds 139 and / or 376

[0732]

[0733] Step a: 6-bromo-4-fluoro-2H-benzotriazole (500 mg, 2.31 mmol, 1.0 eq.) was dissolved in tetrahydrofuran (11.57 mL, 0.2 M), followed by the addition of tert-butyl 4-hydroxypiperidine-1-carboxylate (465.86, 2.31 mmol, 1.0 eq.) and triphenylphosphine (607.11 mg, 2.31 mmol, 1.0 eq.). Then, DIAD (468 mg, 456 μL, 2.31 mmol, 1.0 eq.) was slowly added, and the solution was stirred at RT for 16 hours, then concentrated and injected directly onto a normal phase silica column, purified using 0-100% EtOAc: heptane over 7 minutes. The product was eluted at 70% EtOAc. The identified eluted fractions were collected and concentrated to obtain tert-butyl 4-(6-bromo-4-fluoro-benzotriazol-2-yl)piperidine-1-carboxylate (488.5 mg, 1.14 mmol, yield 49%), which was used as is. MS: m / z 344.9 [M+H] + ; RT 1.05 min (Method 4).

[0734] Step b: tert-Butyl 4-(6-bromo-4-fluoro-benzotriazol-2-yl)piperidine-1-carboxylate (100 mg, 232.93 μmol, 1.0 eq.) was dissolved in water (376 μL, 0.186 M) and dioxane (877 μL, 0.186 M), followed by the addition of 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (76.35 mg, 279.52 μmol, 1.2 eq.) and cesium carbonate (303.6 mg, 931.7 μmol, 4.0 eq.). The solution was then degassed with nitrogen, followed by the addition of Pd(dppf) 2 Cl 2 DCM adduct (15 mg, 18.4 μmol, 0.1 eq), and the solution was heated to 90 ° C for 6 hours, then concentrated and dried, and loaded onto normal phase in dry form and purified by 0-25% MeOH: DCM over 12 minutes. The product eluted at 10% MeOH. The identified elution fractions were collected, combined and concentrated, and then used as is (111.3 mg, 231.9 μmol, yield 99%). MS: m / z 466.2 [M+H] + ; RT 0.74 min (Method 4).

[0735] Step c: tert-Butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-benzotriazol-2-yl]piperidine-1-carboxylate (111.3 mg, 231.9 μmol, 1.0 eq.) was dissolved in DCM (1.16 mL, 0.2 M), followed by the addition of 4M HCl in dioxane (579.7 μL, 2.32 mmol, 10 eq.), and the solution was heated to 40°C for 1 hour. A precipitate was formed, which was further exacerbated by the addition of a few mL of ether. The product was filtered off, washed with ether and dried to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2-(piperidin-4-yl)-2H-benzo[d][1,2,3]triazole (87.1 mg, 216.7 μmol, yield 93%) as a white powder. MS: m / z 366.2 [M+H] + ; RT: 0.44min (Method 4). 1H NMR (400 MHz, methanol-d4) δ ppm 2.54-2.66 (m, 4H) 2.66-2.67 (m, 3H) 2.79-2.83 (m, 3H) 3.34-3.42 (m, 2H) 3.60-3.67 (m, 2H) 5.32-5.40 (m, 1H) 7.98-8.04 (m, 1H) 8.34-8.40 (m, 2H) 8.59-8.62 (m, 1H)

[0736] Step d:

[0737] 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2-(4-piperidinyl)benzotriazole (10 mg, 27.37 umol, 1.0 eq.) was dissolved in acetonitrile (136.83 uL, 0.2 M), followed by the addition of acetaldehyde (3.62 mg, 82.10 umol, 3.0 eq.) and acetic acid (8.22 mg, 136.83 umol, 5.0 eq.). The solution was then stirred for 5 minutes, followed by the addition of sodium cyanoborohydride (3.44 mg, 54.73 μmol, 2.0 eq.). Then, the solution was stirred for 15 minutes, then concentrated, and then redissolved in DMSO, water and methanol, and then purified by HPLC purification method (column: Sunfire C18 100×19mm, 5mm; mobile phase A: MeCN; mobile phase B: H2O; modifier: 0.1% TFA). The eluted fractions after identification were collected, combined and concentrated to obtain 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(1-ethyl-4-piperidinyl)-4-fluoro-benzotriazole (3.9 mg, yield 28.08%, purity 100%) as a white powder, which was registered as is. MS: m / z 394.1[M+H] + ; RT: 2.33min (Method 1). 1 H NMR(600MHz,DMSO-d6)δppm 1.25-1.30(m,3H)2.41-2.43(m,3H)2.43-2.49(m,2H)2.62-2.65(m,3H)3.08-3.18(m,2H)3.19-3.29(m,4H)3.70-3. 76(m,2H)5.26-5.35(m,1H)7.82-7.93(m,1H)7.96-8.04(m,1H)8.06-8.13(m,1H)8.56-8.60(m,1H)9.43-9.55(m,1H)

[0738] Using the procedure described in Example 17 above, other compounds described herein are prepared by substituting the appropriate boronate starting material, suitable reagents and reaction conditions in step b to obtain, for example, a compound selected from the following:

[0739]

[0740]

[0741]

[0742] Example 17 - Compound 140

[0743]

[0744] Step a: To a solution of 1-(tert-butyloxycarbonyl)piperidine-4-carboxylic acid (10 g, 43.62 mmol) in DMF (75 mL) and pyridine (75 mL) was added CDI (7.78 g, 47.9 mmol). The mixture was stirred at 60 ° C for 4 hours. 5-Bromo-3-fluorobenzene-1,2-diamine (8.94 g, 43.62 mmol) was added and the whole mixture was stirred at 30 ° C for 12 hours. The mixture was concentrated under reduced pressure. Then, AcOH (350 mL) was added, and the whole mixture was stirred at 100 ° C for 1 hour. The mixture was concentrated, and then saturated NaHCO was added. 3 Aqueous solution (200 mL). The mixture was extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (300 mL) and purified by Na 2 SO 4 The mixture was filtered and the filtrate was purified by preparative HPLC (column YMC-TriaRT Prep C18 150*40mm*7um; conditions: water (NH 3 H 2 O+NH 4 HCO 3 )-CAN, start B: 36, end B: 76, gradient time (min) 9; flow rate (ml / min): 60) and then lyophilized to give tert-butyl 4-(5-bromo-7-fluoro-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (3.12 g, yield 17%) as a yellow solid. MS: m / z 400.1 [M+H] + .

[0745] Step b: tert-Butyl 4-(5-bromo-7-fluoro-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (39 mg, 0.10 mmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (41 mg, 0.15 mmol), XPhos Pd G3 (8.5 mg, 0.01 mmol) and K 3 PO 4 A mixture of (64 mg, 0.3 mmol) in dioxane (0.8 mL) and water (0.2 mL) was stirred at 60 °C for 2 hours. The reaction solution was washed with brine and extracted with EtOAc (2 mL, 2 times). The combined organics were washed with MgSO 4 Drying and concentration in vacuo afforded tert-butyl 4-(5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate, which was used in the next step without further purification (assumed 100% yield). MS: m / z 465.2 [M+H] + .

[0746] Step c: To a mixture of tert-butyl 4-(5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (46.4 mg, 0.1 mmol) in hexafluoroisopropanol (1 mL) was added TFA (23 μL). After stirring at room temperature for 16 h, the reaction mixture was diluted with 10 mL of DCM and transferred to a 25 mL saturated NaHCO 3 The aqueous solution was placed in a separatory funnel. The layers were separated and the aqueous layer was extracted twice more with DCM. The combined organics were dried over sodium sulfate and concentrated in vacuo to give a crude product, which was purified by preparative HPLC (Waters XSelect CSHPrep C18 5um OBD 30×100mm and 5-65% gradient of ACN-water, 0.1% TFA modifier) ​​to give 6-(7-fluoro-2-(piperidin-4-yl)-1H-benzo[d]imidazol-5-yl)-2,8-dimethylimidazo[1,2-b]pyridazine (4 mg, 11%). MS: m / z 365.2[M+H] + . 1 H NMR (400 MHz, methanol-d 4)δppm 1.83-1.98(m,2H),2.10(br d,J=12.01Hz,2H),2.48(s,3H),2.66(s,3H),2.80(br t,J=11.76Hz,2H),3.06-3.25(m,3H),7.58(s,1H),7.67(d,J=12.01Hz,1H),7.89(s,1H),7.96(s,1H)

[0747] Using the procedure described in Example 17 above, other compounds described herein are prepared by substituting the appropriate boronate or acid equivalent, suitable reagents and reaction conditions in step b to obtain, for example, a compound selected from the following:

[0748]

[0749]

[0750]

[0751] Example 18 - Compounds 131 and 133

[0752]

[0753] Step a: At 20°C, 5-bromo-3-fluoro-pyridin-2-amine (0.5 g, 2.6 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (809 mg, 2.62 mmol) were added to dioxane (10 mL) and H 2 O (2 mL) was added to the solution 2 CO 3 (723 mg, 5.2 mmol) and Pd(dppf)Cl 2 (192 mg, 262 μmol). 2 The mixture was stirred at 90°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by silica column chromatography (PE / EtOAc=1 / 1 to 0 / 1) to give tert-butyl 4-(6-amino-5-fluoro-3-pyridyl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.75 g, 2.51 mmol, yield 95%) as a yellow solid. MS: m / z 294.2 [M+H]+

[0754] Step b: In N 2To a solution of tert-butyl 4-(6-amino-5-fluoro-3-pyridinyl)-3,6-dihydro-2H-pyridine-1-carboxylate (0.1 g, 341 μmol) in MeOH (10 mL) was added Pd / C (36 mg, 34 μmol, 10% purity) at 20°C. 2 The mixture was stirred at 25°C for 2 hours. The residue was purified by preparative HPLC (neutral conditions) to give tert-butyl 4-(6-amino-5-fluoro-3-pyridyl)piperidine-1-carboxylate (0.05 g, 48% yield) as a yellow solid. MS: m / z 296.0 [M+H] +

[0755] Step c: At 25 °C, 2-bromo-1-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)ethanone (150 mg, 559 μmol), tert-butyl 4-(6-amino-5-fluoro-3-pyridyl)piperidine-1-carboxylate (100 mg, 338 μmol) and NaHCO were added. 3 (57mg, 677μmol) in t-BuOH (5mL) solution. The mixture was stirred at 80 ° C for 16 hours. The mixture was concentrated in vacuo to give a crude product. The crude material was purified by silica gel column chromatography (0-100% PE to EtOAc) to give 4-[2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-6-yl]piperidine-1-carboxylic acid tert-butyl ester (100mg, yield 63%) as a yellow solid. MS: m / z 465.7[M+H] +

[0756] Step d: At 25 ° C, 4-[2-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-6-yl]piperidine-1-carboxylic acid tert-butyl ester (100 mg, 215 μmol) was added to a 4M HCL dioxane solution (20 mL). The mixture was stirred at 25 ° C for 0.5 hours. The mixture was concentrated in vacuo to give a crude product. The crude product was purified by preparative HPLC (C18-1150*30mm*5um, water (NH 4 HCO 3 )-ACN as mobile phase, from 23% to 53%, gradient time (min): 15, flow rate (ml / min): 25) to obtain 6-(8-fluoro-6-(piperidin-4-yl)imidazo[1,2-a]pyridin-2-yl)-2,8-dimethylimidazo[1,2-b]pyridazine (30 mg, yield 37%) as a white solid. MS: m / z 365.1 [M+H] +; RT 0.64min (Method 7)

[0757] Step e: A solution of 6-[8-fluoro-6-(4-piperidinyl)imidazo[1,2-a]pyridin-2-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (10 mg, 27.44 μmol), paraformaldehyde (66 mg, 54 μmol, 75 μL) and triethylamine (8 μL, 55 μmol) in 1,2-dichloroethane (5 μL, 55 μmol) and EtOH (5 mL) was stirred at 25 ° C for 0.5 hours. Then, sodium triacetoxyborohydride (12 mg, 55 μmol) was added and stirred for 1 hour. The mixture was concentrated in vacuo to give a crude product, which was purified by preparative HPLC (Boston Prime C18 150*30mm*5um, water (NH 3 H 2 O+NH 4 HCO 3 )-ACN as mobile phase, from 31% to 61%, gradient time (min): 10, flow rate (ml / min): 25) to obtain 6-[8-fluoro-6-(1-methyl-4-piperidinyl)imidazo[1,2-a]pyridin-2-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (6 mg, yield 57%) as a white solid. MS: m / z 379.1 [M+H] + ; RT 1.73min (Method 7)

[0758] Using the procedure described in Example 19 above, other compounds described herein are prepared by substituting the appropriate boronate starting material in step a, the aldehyde in step e, suitable reagents and reaction conditions to obtain, for example, a compound selected from the following:

[0759]

[0760] Example 19 - Compound 127

[0761]

[0762] Step a: To a mixture of 5-bromo-3-fluoropyridin-2-amine (5 g, 26.2 mmol) and pyridine (2.1 g, 26.2 mmol, 2 mL) was added 4-methylbenzene-1-sulfonyl chloride (5 g, 26.2 mmol) at 0°C. 2The reaction mixture was stirred at 100°C for 12 hours under a C atmosphere. The mixture was concentrated, then diluted with water (300 mL), extracted with EtOAc and concentrated to give N-(5-bromo-3-fluoropyridin-2-yl)-4-methylbenzenesulfonamide (6.9 g, 20 mmol, 76% yield) as an off-white solid. MS: m / z 345 [M+H] + ; RT 0.78 min (Method 7).

[0763] Step b: To a solution of tert-butyl 4-(2-bromoacetyl)piperazine-1-carboxylate (98 mg, 319 μmol) and N-(5-bromo-3-fluoro-2-pyridinyl)-4-methyl-benzenesulfonamide (100 mg, 290 μmol) in DMF (2 mL) was added NaHCO 3 (50 mg, 594 μmol). The mixture was stirred at 100 ° C for 16 hours. The reaction mixture was concentrated in vacuo to give a crude product. The crude product was purified by preparative HPLC (column: Boston Green ODS150*30 mm*5 um; conditions: water (FA)-ACN, start B 65, end B 95; gradient time (min): 12; 100% B retention time (min): 2; flow rate (ml / min): 25) to give tert-butyl 4-[2-[(2E)-5-bromo-3-fluoro-2-(p-tolylsulfonylimino)-1-pyridinyl]acetyl]piperazine-1-carboxylate (50 mg, yield 30%) as a yellow solid. MS: m / z 571[M+H] + ; RT 0.692 min (Method 7).

[0764] Step c: To a solution of tert-butyl 4-[2-[(2E)-5-bromo-3-fluoro-2-(p-tolylsulfonylimino)-1-pyridinyl]acetyl]piperazine-1-carboxylate (35 mg, 61 μmol) in DCM (2 mL) was added TFAA (3 g, 14 mmol, 2 mL), and the mixture was stirred at 40 °C for 16 h. The mixture was concentrated in vacuo to give a residue, which was purified by preparative HPLC (Boston Green ODS150*30mm*5um; conditions: water (FA)-ACN, start B 49, end B 59; gradient time (min): 12; 100% B holding time (min): 2; flow rate (ml / min): 25) to give 1-[4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperazin-1-yl]-2,2,2-trifluoro-ethanone (20 mg, yield 83%) as a white solid.

[0765] Step d: In N 2To a solution of 1-[4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperazin-1-yl]-2,2,2-trifluoro-ethanone (20 mg, 50 μmol) in dioxane (3 mL) and water (0.5 mL) was added 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (14 mg, 51 μmol), K 2 CO 3 (21 mg, 152 μmol) and Pd(dppf)Cl 2 (4 mg, 5 μmol). The mixture was stirred at 80°C for 2 hours. The mixture was concentrated and then water (50 mL) was added. The mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (30 mL) and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo to obtain a residue, which was purified by preparative HPLC (column: Boston Prime C18 150*30mm*5um; conditions: water (NH 3 H 2 O+NH 4 HCO 3 )-ACN, starting B 44, ending B 74; gradient time (min): 10; 100% B holding time (min): 2; flow rate (ml / min): 25) to obtain 6-(8-fluoro-2-piperazin-1-yl-imidazo[1,2-a]pyridin-6-yl)-2,8-dimethyl-imidazo[1,2-b]pyridazine (8 mg, yield 44%). MS: m / z 366.0 [M+H] + ; RT 1.2 min (Method 7).

[0766] Example 20 - Compound 150

[0767]

[0768] Step a: In N 2 4-(6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (60 mg, 150.3 μmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (53.4 mg, 195.36 μmol), Pd(dppf)Cl 2A mixture of DCM (12.27 mg, 15.03 μmol), dicesium carbonate (146.8 mg, 450.8 μmol) in dioxane (1.2 mL) and water (300 μL) was stirred for 4 h. The mixture was filtered through Celite / MgSO 4 Filter (DCM / EtOAc eluent), concentrate, and use the crude product in the next step (assumed 100% yield). MS: m / z 466.3 [M+H] +

[0769] Step b: A mixture of tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]piperidine-1-carboxylate (70 mg, 150.37 μmol) and HCl (4M in dioxane, 300 μL) in DCM (3.0 mL) was stirred at RT for 3 hours. The mixture was concentrated and then purified by preparative HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H 2 O; modifier: 0.1% TFA) to obtain 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(4-piperidinyl)-[1,2,4]triazolo[1,5-a]pyridine (16.4 mg, yield 23%). MS: m / z 366.2 [M+H] + ; RT: 0.38min (Method 4)

[0770] Using the procedure described in Example 20 above, other compounds described herein are prepared by substituting the appropriate boronate ester, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0771]

[0772] Example 21 - Compound 294 and / or 264

[0773]

[0774] Step a: In N 2 To a solution of 6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-amine (200 mg, 869 μmol) in dioxane (20 mL) and water (1 mL) was added 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (237 mg, 869 μmol), Pd(dppf)Cl2 (64 mg, 87 μmol) and K 2 CO3 (360 mg, 2.61 mmol). The mixture was stirred at 90°C for 2 hours. The mixture was concentrated and then water (80 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo to give the crude product. The crude product was purified by Combi-Flash (DCM / MeOH=10 / 1) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-amine (200 mg, 674.99 μmol, yield 77.64%) as a brown solid. MS: m / z 297.2 [M+H] + ; RT: 0.1237min (Method 10)

[0775] Step b: 1-tert-Butyloxycarbonylazetidine-3-carboxylic acid (326 mg, 1.62 mmol) and EDCI (388 mg, 2 mmol) were added to a solution of 6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-amine (400 mg, 1.35 mmol) in pyridine (10 mL), and the mixture was stirred at 90 ° C for 1 hour. Then, the mixture was concentrated and water (80 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue, which is purified by Combi-Flash (DCM / MeOH=20 / 1) to give tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (250 mg, 521 umol, 39% yield) as a yellow solid. MS: m / z 480.3 [M+H] + ; RT: 0.798min (Method 4)

[0776] Step c: To a solution of tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (50 mg, 104 umol) in DCM (2 mL) was added TFA (2 mL), and the mixture was stirred at 20 ° C for 1 hour. The mixture was concentrated in vacuo and purified by preparative HPLC (FA) to give N-[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]azetidine-3-carboxamide (22 mg, 57 umol, 55% yield) as a white solid. MS: m / z 380.0[M+H] + ; RT: 0.777min (Method 7)

[0777] Step d: N-[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]azetidine-3-carboxamide (30 mg, 79 umol) and cyclobutanone (17 mg, 237 umol, 18 uL) were added to DCE / EtOH (4 mL) and stirred at 20 ° C for 20 minutes. Sodium triacetoxyborohydride (50 mg, 237 umol) was added to the reaction mixture and stirred at 20 ° C for 12 hours. The reactant was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give 1-cyclobutyl-N-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]azetidine-3-carboxamide (4.6 mg, 10 umol, yield 13%, purity 97%) as a yellow solid. MS: m / z 434.1 [M+H] + ; RT: 1.23 min (Method 8); 1H NMR: (400 MHz, methanol-d4) δ ppm = 9.05 (s, 1H), 8.34 (d, J = 2.8 Hz, 1H), 7.94 (s, 1H), 7.81 (d, J = 12.4 Hz, 1H), 7.60 (s, 1H), 3.73-3.68 (m, 2H), 3.56-3.48 (m, 3H), 2.68 (s, 3H), 2.64-2.58 (m, 1H), 2.49 (s, 3H), 1.01 (d, J = 6.4 Hz, 6H).

[0778] Using the procedure described in Example 21 above, other compounds described herein are prepared by substituting the appropriate boronate ester, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0779]

[0780]

[0781]

[0782]

[0783] Example 22 - Compound 126

[0784]

[0785] Step a: tert-Butyl 4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (100 mg, 251 μmol) was dissolved in DCM (2.5 mL), NCS (34 mg, 251 μmol) was added, and stirred at room temperature for 30 minutes. The resulting product was purified by silica gel flash chromatography using 0-100% EtOAc / heptane gradient elution to give tert-Butyl 4-(6-bromo-3-chloro-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (67 mg, 61% yield) MS: m / z 432[M+H]+.

[0786] Step b: 4-(6-bromo-3-chloro-8-fluoro-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (39.5 mg, 91.24 μmol) was dissolved in dioxane (1.5 mL) and water (0.8 mL) with 2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (26.0 mg, 100.4 μmol), cesium carbonate (59.5 mg, 182.4 μmol) and di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (5.9 mg, 9.12 μmol). The mixture was washed with N 2 Degas and heat in microwave to 90°C for 2 hours. The resulting mixture was cooled to room temperature and purified by silica gel flash chromatography using a 0-100% EtOAc / heptane gradient. MS: m / z 485 [M+H] + .

[0787] Step c: tert-Butyl 4-[3-chloro-8-fluoro-6-(2-methylimidazo[1,2-b]pyridazin-6-yl)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (5.6 mg, 12 μmol) was dissolved in DCM (1 mL), and HCl (4M in dioxane, 57 μL) was added and stirred at room temperature for 1 hour. The resulting mixture was concentrated to dryness to give 6-[3-chloro-8-fluoro-2-(4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]-2-methyl-imidazo[1,2-b]pyridazine (4 mg, 90% yield). 1 HNMR(500MHz, methanol-d4)δppm 2.00-2.18(m,4H)2.57(s,3H)3.06-3.16(m,3H)3.25-3.32(m,1H)3.43-3.52(m,4H)7.92(br d,J=11.60Hz,1H)8.32(s,1H)8.36-8.47(m,2H)8.87-8.93(m,1H)MS:m / z385[M+H] + .

[0788] Example 23 - Compounds 154 and 456

[0789]

[0790] Step a: A mixture of 2-amino-5-bromo-3-fluoro-phenol (360 mg, 1.75 mmol) and 1-tert-butoxycarbonylpiperidine-4-carboxylic acid (400.6 mg, 1.75 mmol) in PPA (3 mL) was stirred at 160° C. for 0.5 h. This was used directly in the next step without further purification.

[0791] [M+2+H]=301.0

[0792] Step b: A solution of 6-bromo-4-fluoro-2-(4-piperidinyl)-1,3-benzoxazole (400 mg, 1.34 mmol) and TEA (1.34 mmol, 186 μL), tert-butyloxycarbonyl tert-butyl carbonate (291.8 mg, 1.34 mmol, 307.2 μL) in THF (15 mL) and water (40 mL) was stirred at 0°C for 0.5 hours. The mixture was concentrated and then water (50 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were purified by Na 2 SO 4Dry, filter and concentrate. The crude material was purified by silica gel column chromatography (PE / EtOAc=5 / 1 to 3 / 1, TLC: PE / EtOAc=3 / 1) to give tert-butyl 4-(6-bromo-4-fluoro-1,3-benzoxazol-2-yl)piperidine-1-carboxylate (366 mg, yield 68%) as a yellow solid. [M-tBu+2+H]=344.8

[0793] Step c: To a solution of tert-butyl 4-(6-bromo-4-fluoro-1,3-benzoxazol-2-yl)piperidine-1-carboxylate (50 mg, 125.2 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (34.2 mg, 125.2 μmol) in dioxane (3 mL) and water (1 mL) was added Pd(dppf)Cl2 (9.16 mg, 12.52 μmol) and K 2 CO 3 (34.6 mg, 250.4 μmol). The mixture was washed with N 2 The mixture was degassed 3 times and stirred at 80° C. for 2 hours. The reaction mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC (NH 3 .H 2 O modifier) ​​to give tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-1,3-benzoxazol-2-yl]piperidine-1-carboxylate (30 mg, yield 51%) as a white solid. [M+H]=466.3

[0794] Step d: To a solution of tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-1,3-benzoxazol-2-yl]piperidine-1-carboxylate (20 mg, 42.9 μmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (1 mL) was added TFA (14.70 mg, 128.8 μmol, 9.87 μL). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was washed with CH 3CN (2mL), and purified by preparative HPLC (column: Boston Green ODS150*30mm*5um; conditions: water (FA)-ACN, start B 42, end B 72; gradient time (min): 12; 100% B holding time (min): 2; flow rate (ml / min): 25) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2-(4-piperidinyl)-1,3-benzoxazole (11.2 mg, yield 71%) as a white solid. [M+H]=366.1; 1 H NMR (400 MHz, methanol-d4) δ: 8.16 (s, 1H), 7.96 (s, 1H), 7.88 (m, 1H), 7.66 (s, 1H), 3.80-3.75 (m, 1H), 3.20-3.10 (m, 2H), 2.80-2.70 (m, 2H), 2.69 (s, 3H), 2.51 (s, 3H), 2.25-2.15 (m, 2H), 2.20-2.10 (m, 2H).

[0795] Using the procedure described in Example 23 above, other compounds described herein are prepared by substituting the appropriate boronate ester, suitable reagents and reaction conditions in step c to obtain, for example, a compound selected from the following:

[0796]

[0797]

[0798] Example 25 - Compound 439

[0799]

[0800] Step a: At 25°C, 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-(4-piperidinyl)-[1,2,4]triazolo[1,5-a]pyridine (30 mg, 82 umol), 1-bromo-2-methoxy-ethane (11 mg, 82 umol, 8 uL) and Cs 2 CO 3(54mg, 164umol) in DMF (3mL), the mixture was stirred at 90 ° C for 1 hour. The mixture was concentrated in vacuo to give a crude product. The crude product was purified by preparative HPLC (Boston Prime C18 150*30mm*5um, water (NH3H2O+NH4HCO3)-ACN as mobile phase, from 29% to 59%, gradient time (min): 10, flow rate (ml / min): 25) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-2-[1-(2-methoxyethyl)-4-piperidinyl]-[1,2,4]triazolo[1,5-a]pyridine (9.3mg, 21.96umol, yield 26.75%, purity 100%) as a white solid. MS: m / z 424.2[M+H] + ; RT: 1.612min (Method 10)

[0801] Using the procedure described in Example 12 above, other compounds described herein are prepared by substituting appropriate starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0802]

[0803] Example 26 - Compounds 443 and 453

[0804]

[0805] Step a: At 25 ° C, O-(2,4-dinitrophenyl)hydroxylamine (2.1 g, 10 mmol) was added to a solution of 5-bromo-3-fluoro-pyridin-2-amine (2 g, 10 mmol) in MeCN (15 mL). The mixture was stirred at 40 ° C for 16 hours. The mixture was filtered to remove the solvent to give 5-bromo-3-fluoro-pyridin-1-ium-1,2-diamine (3 g, crude) as a yellow solid. Then, 5-bromo-3-fluoro-pyridin-1-ium-1,2-diamine (3 g, crude) was dissolved in DMSO (6 mL) for storage. MS: m / z 206.0 [M+H] + ; RT: 0.463min (Method 10)

[0806] Step b: KOH (2M, 355uL) was added to a solution of 5-bromo-3-fluoro-pyridine-1,2-diamine (98mg, 473umol, 1.5mL) and (1S, 5R)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (100mg, 473umol) in MeOH (4mL), and the mixture was stirred at 25°C for 1 hour, and then the reaction mixture was distributed between EtOAc (30mL) and water (5mL). After quenching the reaction, the reaction mixture was poured into a separatory funnel and separated. Then, the mixture was dissolved in MeOH and filtered, and purified by preparative HPLC (column: Boston Green ODS150*30mm*5um; mobile phase: 40% to 80% water (FA)-ACN) to obtain (1S,5R)-6-(6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (97 mg, 243umol, yield 51%) as a white solid. MS: m / z 397.1[M+H] + ; RT: 1.147min (Method 7)

[0807] Step c: To a solution of (1S,5R)-6-(6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (40 mg, 100 umol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (33 mg, 120 umol) in dioxane (3 mL) and water (1 mL) was added Pd(dppf)Cl 2 (1.5mg, 2umol) and K 2 CO 3 (28 mg, 201 umol). The mixture was stirred at 90°C for 16 hours under nitrogen. The mixture was extracted with EtOAc (15 mL x 3) and washed with Na 2 SO 4 Dry. The combined organic phases were filtered and concentrated under reduced pressure. The residue was purified by silica gel column (40% to 100% EtOAc: PE) to give (1S, 5R)-6-[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (30 mg, 64 umol, 64% yield) as a yellow solid. MS: m / z 464.2 [M+H] + ;RT:1.999min(Method 10)

[0808] Step d: To a solution of (1R,5S)-6-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (15 mg, 32 umol) in hexafluoroisopropanol (4 mL) was added TFA (18 mg, 161 umol, 12 uL), and the mixture was stirred at 25 °C for 1 hour. The solution was evaporated under reduced pressure on a water bath, and then the mixture was dissolved in MeOH and filtered, and purified by preparative HPLC (column: Boston Green ODS150*30mm*5um; mobile phase: 0% to 15% water (FA)-ACN) to give 2-[(1R, 5S)-3-azabicyclo[3.1.0]hexan-6-yl]-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine (10 mg, 28 umol, yield 86%) as a white solid. MS: m / z 364.1[M+H] + ; RT: 1.213min (Method 10)

[0809] Step e: To a solution of 2-[(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine (16 mg, 43 μmol) and paraformaldehyde (51 mg, 43 μmol, 58 μL) in MeOH (2 mL) was added acetic acid (13 mg, 215 μmol, 12 μL), and the mixture was stirred at 25° C. for 20 minutes. Sodium cyanoborohydride (8 mg, 129 μmol) was added and the mixture was stirred at 25° C. for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-2-[(1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]-[1,2,4]triazolo[1,5-a]pyridine (9 mg, 25 μmol, 57% yield) as a yellow solid. MS: m / z 378.2 [M+H] + ; RT: 1.233min (Method 10)

[0810] Using the procedure described in Example 12 above, other compounds described herein are prepared by substituting appropriate starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0811]

[0812]

[0813] Example 27 - Compound 539

[0814]

[0815] Step a: To a solution of tert-butyl (1S,5R)-6-(2-bromoacetyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.64 mmol) in t-BuOH (10 mL) was added NaHCO 3 (276mg, 3.29mmol, 127uL) and 5-bromo-3-methoxy-pyridine-2-amine (333mg, 1.64mmol). The mixture was stirred at 80 ° C for 12 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by flash silica gel chromatography (PE / EtOAc=10 / 1 to 0 / 1, TLC: PE / EtOAc=1 / 1, Rf=0.45) to give the product. Compound (1S, 5R)-6-(6-bromo-8-methoxy-imidazo[1,2-a]pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (323mg, 791umol, 48% yield) was obtained as a yellow solid. MS: m / z 408.0[M+H] + ; RT: 0.375min (Method 9)

[0816] Step b: To a stirred solution of (1S,5R)-6-(6-bromo-8-methoxy-imidazo[1,2-a]pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (70 mg, 171 umol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (47 mg, 171 umol) in dioxane (5 mL) was added K 2 CO 3 (71 mg, 514 umol) and Pd(dppf)Cl 2(13 mg, 17 umol). The reaction mixture was stirred at 90 ° C for 1 hour. The mixture was filtered and concentrated to give a residue. The residue was purified by preparative HPLC purification method (neutral conditions). The compound (1S, 5R) -6- [6- (2,8-dimethylimidazo [1,2-b] pyridazine -6- base) -8-methoxy-imidazo [1,2-a] pyridin-2-yl] -3- azabicyclo [3.1.0] hexane -3- carboxylic acid tert-butyl ester (30 mg, 62 umol, yield 36%) was obtained as a white solid. MS: m / z 475.3 [M + H] + ; RT: 0.283min (Method 9)

[0817] Step c: (1S,5R)-6-[6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine-6-yl]-8-methoxy-imidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (12 mg, 23 umol) was added to a solution of HCl / EtOAc (2 mL). The mixture was stirred at 25 °C for 8 hours. The mixture was filtered and concentrated to give a residue. The crude compound was used in the next step without further purification. The compound 6-[2-[(1S,5R)-3-azabicyclo[3.1.0]hex-6-yl]-8-methoxy-imidazo[1,2-a]pyridin-6-yl]-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (8 mg, 19.5 umol, yield 82%) was obtained as a white solid. MS: m / z 411.1 [M+H] + ; RT: 0.241min (Method 9)

[0818] Step d: To a stirred solution of 6-[2-[(1S, 5R)-3-azabicyclo[3.1.0]hex-6-yl]-8-methoxy-imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (20 mg, 53 umol) and paraformaldehyde (64 mg, 53 umol, 73 uL) in DCE / EtOH (6 mL), TEA (16 mg, 160 umol, 23 uL) was added and stirred at 20 ° C for 15 minutes. After addition, sodium triacetoxyborohydride (23 mg, 107 umol) was added to the mixture and stirred at 20 ° C for 2 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by preparative HPLC purification (neutral conditions). The compound 6-[8-methoxy-2-[(1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (8 mg, 20 umol, yield 37%) was obtained as a yellow solid. MS: m / z 389.1 [M+H] + ; RT: 0.183min (Method 9)

[0819] Using the procedure described in Example 1 above, other compounds described herein are prepared by substituting the appropriate bromoketone starting material in step a, the appropriate boronate ester or acid equivalent in step b, suitable reagents and reaction conditions to obtain, for example, a compound selected from the following:

[0820]

[0821] Example 28 - Compound 537

[0822]

[0823] Step a: tert-Butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (400.33 mg, 1.31 mmol, 1.25 eq.) and 5-bromo-3-(difluoromethoxy)pyridin-2-amine (250 mg, 1.05 mmol, 1.0 eq.) were dissolved in water (5.23 mL), heated to 80°C for 16 hours, then concentrated and loaded onto normal phase silica in dry form and purified with 0-25% MeOH:DCM over 12 minutes. Deboc material was eluted at 20% methanol and boc material was eluted at 4% methanol. The identified fractions were collected, concentrated, quantified and used as is. MS: m / z 392.1 [M+H-tBu] + ; RT 0.67min (Method 4).

[0824] Step b: tert-Butyl 4-[6-bromo-8-(difluoromethoxy)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (98.7 mg, 221 umol, 1.0 eq.) was dissolved in dioxane (1 mL, 0.2 M) and water (1 mL, 0.2 mL), followed by the addition of 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (66.4 mg, 239 umol, 1.1 eq.) and cesium carbonate (216.2 mg, 663 umol, 3 eq.). The solution was then thoroughly degassed with nitrogen, followed by the addition of Pd(dppf)Cl2 DCM (18 mg, 22.1 umol, 0.1 eq.). The solution was then heated at 80 °C for 2 h and concentrated to give the crude product, assuming a 100% yield.

[0825] Step c: tert-Butyl 4-[8-(difluoromethoxy)-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)imidazo[1,2-a]pyridin-2-yl]piperidine-1-carboxylate (113.4 mg, 221.2 umol, 1.0 eq.) was dissolved in DCM (3 mL, 0.07 M), followed by the addition of 4M HCl in dioxane (80.63 mg, 2.21 mmol, 10.0 eq.). The solution was then stirred at 50° C. for 2 hours, then concentrated, then redissolved in DMSO, filtered and purified by HPLC purification (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; modifier: 0.1% TFA). The identified eluted fractions were collected, combined and concentrated to obtain 6-[8-(difluoromethoxy)-2-(4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (18.3 mg, yield 15.7%) as a yellow oil. MS: m / z 413.3 [M+H] + ; RT 1.88min (Method 1). 1H NMR(600MHz,DMSO-d6)δppm 1.87-1.97(m,2H)2.15-2.19(m,2H)2.19-2.49(m,3H)2.52-2.73(m,3H)3.05-3.20(m,4H)3.43-3.57(m,1H)7.66-7.68(m,1H) 7.69-7.71(m,1H)7.72-7.75(m,1H)7.95-7.98(m,1H)8.12-8.16(m,1H)8.27-8.36(m,1H)8.54-8.65(m,1H)9.19-9.23(m,1H)

[0826] Using the procedure described in Example 1 above, other compounds described herein are prepared by substituting the appropriate bromoketone starting material in step a, the appropriate boronate ester or acid equivalent in step b, suitable reagents and reaction conditions to obtain, for example, a compound selected from the following:

[0827]

[0828] Example 29 - Compound 549

[0829]

[0830] Step a: To a solution of 5-bromo-3-(trifluoromethoxy)pyridin-2-amine (250 mg, 0.97 mmol) and (2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid (265.7 mg, 0.97 mmol) in dioxane (4.6 mL) and water (1.6 mL) was added Cs 2 CO 3 (950.8 mg, 2.92 mmol) and Pd(dppf)Cl 2 (79.4 mg, 97.2 μmol). The mixture was stirred at 90°C for 16 hours under nitrogen. The mixture was extracted with EtOAc (15 mL x 3) and washed with Na 2 SO 4 The product was dried. The combined organic phase was filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0% to 20% MeOH: DCM) to give 5-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-3-(trifluoromethoxy)pyridin-2-amine (247.2 mg, 0.76 mmol, 79% yield) as a yellow solid. MS: m / z 324.1 [M+H] + .

[0831] Step b: To a solution of tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (56.8 mg, 185.6 μmol) in t-BuOH (2 mL) was added 5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-(trifluoromethoxy)pyridin-2-amine (60 mg, 185.6 μmol) and NaHCO 3(46.8 mg, 556.8 μmol), and the mixture was stirred at 80 ° C for 16 hours. The mixture was concentrated in vacuo to give a residue, which was purified by flash silica gel chromatography (0% to 10% MeOH: DCM) to give tert-butyl 4-(6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-(trifluoromethoxy)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (69.2 mg, 70% yield) as a yellow solid. MS: m / z 531.3 [M+H] + .

[0832] Step c: 4-(6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-(trifluoromethoxy)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (69.2 mg, 130.4 μmol) was dissolved in 4M HCl in dioxane (0.26 mL) and DCM (2 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated in vacuo and purified by preparative HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H 2 O; modifier: 0.1% TFA) to give 2,8-dimethyl-6-(2-(piperidin-4-yl)-8-(trifluoromethoxy)imidazo[1,2-a]pyridin-6-yl)imidazo[1,2-b]pyridazine trifluoroacetate (1.3 mg, yield 1.8%) as a white solid. MS: m / z 431.3 [M+H] + .

[0833] Example 30 - Compounds 551 and 552

[0834]

[0835] Step a: 5-Bromopyridin-2-amine (500 mg, 2.89 mmol) was dissolved in ACN (3.47 mL) and toluene (2.31 mL). Sodium bicarbonate (242 mg, 2.89 mmol) was added followed by tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (884 mg, 2.89 mmol). The mixture was stirred at 90 °C overnight. The resulting product was concentrated and purified by flash chromatography using a 0-100% EtOAc / heptane gradient. MS: m / z 415.2 [M+H] + ; RT: 0.86min (Method 4)

[0836] Step b: tert-Butyl 4-(6-bromoimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (200 mg, 525.93 umol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (158 mg, 578 umol) were dissolved in dioxane (1.58 mL) and water (1 mL) with PdCl 2 (dippf) (31 mg, 52 umol) and cesium carbonate (514 mg, 1.6 mmol) were mixed. The mixture was washed with N 2 Purge, then heat in microwave at 90 °C for 1 hour. The solution was diluted with water, extracted with EtOAc, and dried over sodium sulfate. The resultant was dissolved in 2 mL of DCM and treated with 2 ml of 4N HCl / dioxane. The solution was then stirred at room temperature for another 3 hours. The solution was concentrated and purified by acidic preparative HPLC. MS: m / z 347.1 [M+H] + ; RT 0.54 min (Method 3).

[0837] Step c: 2,8-dimethyl-6-[2-(4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]imidazo[1,2-b]pyridazine (10 mg, 28.9 umol) was dissolved in ACN (1 mL), paraformaldehyde (35 mg, 28.9 umol, 40 uL), acetic acid (17 mg, 289 umol, 17 uL), sodium cyanoborohydride (6 mg, 87 umol) and heated to 70 ° C overnight. The resultant was concentrated and purified by acidic preparative HPLC. MS: m / z 361.1 [M+H] + ; RT 1.032 min (Method 10).

[0838] Using the procedure described in Example 1 above, other compounds described herein are prepared by substituting the appropriate bromoketone starting material in step a, the appropriate boronate ester or acid equivalent in step b, suitable reagents and reaction conditions to obtain, for example, a compound selected from the following:

[0839]

[0840] Example 31 - Compound 557

[0841]

[0842] Step a: At 0°C, tert-butyl 4-(6-bromoimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate (270 mg, 710 umol) was dissolved in chloroform (4 mL). Then, DMAP (87 mg, 710 umol) was added, followed by 1-(chloromethyl)-4-fluoro-1,4-diazobicyclo[2.2.2]octane; bistetrafluoroborate (503 mg, 1.42 mmol). The reaction was stirred at 0°C for 2 hours, then the reaction was heated to 55°C for 6 hours, quenched with saturated aqueous sodium carbonate solution and extracted with EtOAc. The crude product was purified by RPHPLC using an acidic gradient of 0-70% ACN-water. MS: m / z 397.0 [M+H] + ; RT: 0.70min (Method 4).

[0843] Step b: 4-(6-bromo-3-fluoro-imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester (45 mg, 113 umol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (34 mg, 124 umol) were reacted with PdCl 2 (dippf) (7 mg, 11.3 umol) and cesium carbonate (110 mg, 339 umol) were dissolved in dioxane (1.6 mL) and water (1.1 mL). 2 Degas and heat in microwave at 90°C for 1 hour. Extract with water / EtOAc and dry with sodium sulfate. Concentrate the organics and dissolve in DCM (2 mL) and treat with 4N HCl in dioxane (2 mL). Stir the solution at room temperature for 3 hours, then concentrate and purify by acidic preparative HPLC. MS: m / z 365.1 [M+H] + ; RT: 0.68min (Method 3).

[0844] Example 32 - Compounds 350 and 363

[0845]

[0846] Step a: To a solution of tert-butyl 4-(p-tolylsulfonyloxy)piperidine-1-carboxylate (1.36 g, 3.83 mmol) in DMF (10 mL) was added K 2 CO 3 (1.59 g, 11.49 mmol) and 5-bromo-7-fluoro-2H-indazole (823 mg, 3.83 mmol). The mixture was stirred at 100 °C for 12 hours. The reaction mixture was washed with H 2O (40 mL), and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (30 mL×2) and purified by Na 2 SO 4 Dry, filter and concentrate under reduced pressure to obtain a residue. The residue is purified by flash silica gel chromatography (PE / EtOAc=10 / 1 to 5 / 1, TLC: PE / EtOAc=5 / 1, Rf=0.30) to obtain the product. Compound 4-(5-bromo-7-fluoro-indazole-2-yl)piperidine-1-carboxylic acid tert-butyl ester (492 mg, 1.24 mmol, yield 32%) is obtained as a yellow oil. MS: m / z 342.0 [M-56] + ; RT: 0.518 min (Method 9).

[0847] Step b: To a solution of tert-butyl 4-(5-bromo-7-fluoro-indazol-2-yl)piperidine-1-carboxylate (60 mg, 150 umol) in dioxane (2 mL) was added KOAc (29 mg, 301 umol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (46 mg, 181 umol) and PdCl 2 (dppf) (22 mg, 30 umol). 2 The mixture was stirred at 90°C for 2 hours. The crude compound was used in the next step without further purification. MS: m / z 446.3 [M+H] + ; RT: 0.813 min (Method 7).

[0848] Step c: tert-Butyl 4-[7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazol-2-yl]piperidine-1-carboxylate (100 mg, 224 μmol) in dioxane (2 mL) and H 2 Cs was added to the solution in O (1 mL) 2 CO 3 (219.5 mg, 673 μmol), 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (32 mg, 134 μmol) and PdCl 2 (dppf) (10 mg, 13 μmol). 2 The mixture was stirred at 90°C for 2 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 20:1 to 1:1) to obtain the product as a white solid. MS: m / z 501.0 [M+H] +; RT: 0.80min (Method 4).

[0849] Step d: To a solution of tert-butyl 4-(5-(8-(difluoromethyl)-2-methylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-2H-indazol-2-yl)piperidine-1-carboxylate (70 mg, 139.86 μmol) in DCM (2 ml) was added 4N HCl in dioxane (34 μL). The mixture was stirred at 25 °C for 1 hour. The mixture was concentrated to give a residue. The crude compound was used in the next step without further purification. MS: m / z 400.9 [M+H] + ; RT:0.0.55min (Method 4).

[0850] Step e: 8-(Difluoromethyl)-6-[7-fluoro-2-(4-piperidinyl)indazol-5-yl]-2-methyl-imidazo[1,2-b]pyridazine (43 mg, 109 umol) was dissolved in THF (1 mL) with paraformaldehyde (132 mg, 109 umol, 149 uL), acetic acid (66 mg, 1.10 mmol, 63 uL), and sodium cyanoborohydride (21 mg, 329 umol). The mixture was warmed to 70 ° C and stirred overnight. The resultant was diluted with water, extracted with EtOAc and concentrated. The crude product was purified by FCC using a 0-100% EtOAc heptane gradient to obtain the compound. MS: m / z 415.2 [M+H] + ; RT: 1.83min (Method 4).

[0851] Using the procedure described in Example 12 above, other compounds described herein are prepared by substituting appropriate starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0852]

[0853]

[0854] Example 33 - Compound 196

[0855]

[0856] Step a: In N 2To a solution of 6-bromo-2-cyclopent-3-en-1-yl-8-fluoro-imidazo[1,2-a]pyridine (30 mg, 106 umol) in dioxane (5 mL) was added 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (35 mg, 128 umol), Pd(dppf)Cl2 (8 mg, 11 umol) and K 2 CO 3 (30 mg, 213 umol). The mixture was stirred at 90°C for 2 hours. The reaction mixture was concentrated, and then water (80 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue, which is purified by preparative HPLC (FA) to give 6-(2-cyclopent-3-en-1-yl-8-fluoro-imidazo[1,2-a]pyridin-6-yl)-2,8-dimethyl-imidazo[1,2-b]pyridazine (6.6 mg, 19.00 umol, 17.80% yield) as a yellow solid. MS: m / z 348.1 [M+H] + ; RT: 1.88min (Method 10)

[0857] Example 34 - Compound 226

[0858]

[0859] Step a: At 25 ° C, to a solution of 6-bromo-2-cyclopent-3-ene-1-yl-8-fluoro-imidazo[1,2-a]pyridine (200 mg, 711 μmol) in acetone (15 mL) and water (15 mL), dipotassium NMO (166 mg, 1.42 mmol); osmium dioxide (dioxide); dihydrate (52 mg, 142 μmol). The reaction was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated in vacuo to give the crude product 4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)cyclopentane-1,2-diol (200 mg, 634 μmol, yield 89%) as a gray solid. MS: m / z 316.9 [M+2H] + ; RT: 1.022min (Method 10)

[0860] Step b: At 25 ° C, sodium periodate (271 mg, 1.27 mmol) was added to a solution of 4-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)cyclopentane-1,2-diol (200 mg, 634.64 μmol) in dioxane (10 mL) and water (10 mL). The reaction was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated in vacuo to give a crude product. The crude product was purified by silica gel column chromatography (PE / EtOAc=5 / 1 to 2 / 1) to give 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)glutaraldehyde (180 mg, 574.86 μmol, 90% yield) as a yellow solid. MS: m / z 314.9 [M+2H] + ; RT: 1.035min (Method 10)

[0861] Step c: At 25 ° C, acetic acid (46 mg, 766 μmol, 44 μL) was added to a mixture of 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)glutaraldehyde (80 mg, 255.49 μmol) and 1-methylcyclopropylamine (22 mg, 306.59 μmol) in EtOH (5 mL) and DCE (5 mL) in one portion. After 30 minutes, sodium triacetoxyborohydride (162 mg, 766 μmol) was added. The mixture was concentrated and then water (60 mL) was added. The mixture was extracted with DCM (50 mL×3). The combined organic layer was purified by Na 2 SO 4 Dry, filter and concentrate. The crude material was purified by preparative HPLC (column Phenomenex Gemini-NX 150*30mm*5um; condition: water (NH 4 HCO 3 )-ACN; start B 40; end B 70; gradient time (min) 11; 100% B hold time (min) 2; flow rate (ml / min) 25) to obtain 6-bromo-8-fluoro-2-[1-(1-methylcyclopropyl)-4-piperidinyl]imidazo[1,2-a]pyridine (20 mg, 56.78 μmol, yield 22%) as a yellow solid. MS: m / z 352.1 [M+H] + ; RT: 0.687min (Method 10)

[0862] Step d: In N 2To a mixture of 6-bromo-8-fluoro-2-[1-(1-methylcyclopropyl)-4-piperidinyl]imidazo[1,2-a]pyridine (20 mg, 56.78 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (17 mg, 62.46 μmol) in dioxane (5 mL) was added Pd(dppf)Cl in one portion at 25 °C under atmospheric pressure. 2 (5 mg, 5.68 μmol), K 2 CO 3 (24 mg, 170.34 μmol). The mixture was stirred at 90°C for 16 hours. The mixture was concentrated and then water was added. The mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine and purified by Na 2 SO 4 Dry, filter and concentrate. The crude material was purified by preparative HPLC (column: Phenomenex Gemini-NX 150*30mm*5um; conditions: water (NH 4 HCO 3 )-ACN; start B 40; end B 70; gradient time (min) 11; 100% B hold time (min) 2; flow rate (ml / min) 25) to give 6-[8-fluoro-2-[1-(1-methylcyclopropyl)-4-piperidinyl]imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (3.7 mg, 8.84 μmol, yield 15%) as a yellow solid. MS: m / z 419.3[M+H] + ; RT: 1.935min (Method 10)

[0863] Using the procedure described in Example 12 above, other compounds described herein are prepared by substituting appropriate starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0864]

[0865] Example 35 - Compound 207

[0866]

[0867] Step a: 6-[8-fluoro-2-(4-piperidinyl)imidazo[1,2-a]pyridin-6-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (30 mg, 82 umol) and (1-ethoxycyclopropyloxy)-trimethyl-silane (43 mg, 246 umol, 49.65 uL) were dissolved in THF (2 mL) and treated with deuterated 2,2,2-trideuterium acetate (52 mg, 823 umol, 50 uL) and sodium cyanoborodeuteride (16 mg, 246.97 umol). The mixture was then stirred at 65 ° C overnight. The reactant was purified by preparative HPLC (TFA). MS: m / z 406.3 [M+H] + ; RT: 0.86min (Method 3)

[0868] Example 36 - Compound 555

[0869]

[0870] Step a: To a solution of 5-bromo-3-methylpyridin-2-amine (250 mg, 1.34 mmol) and (2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid (365.1 mg, 1.34 mmol) in dioxane (4.6 mL) and water (1.6 mL) was added Cs 2 CO 3 (1.31 g, 4.01 mmol) and Pd(dppf)Cl 2 (109.2 mg, 133.7 μmol). The mixture was stirred at 90°C for 16 hours under nitrogen. The mixture was extracted with EtOAc (15 mL x 3) and washed with Na 2 SO 4 The residue was purified by flash silica gel chromatography (0% to 20% MeOH: DCM) to give 5-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-3-methylpyridin-2-amine (263.7 mg, 1.04 mmol, 78% yield) as a yellow solid. MS: m / z 254.1 [M+H] + .

[0871] Step b: To a solution of tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (48.4 mg, 157.9 μmol) in t-BuOH (2 mL) was added 5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-3-methylpyridin-2-amine (40 mg, 157.9 μmol) and NaHCO 3(39.8 mg, 473.7 μmol), and the mixture was stirred at 80 ° C for 16 hours. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in 4M HCl in dioxane (0.39 mL) and DCM (2 mL). The mixture was stirred at 25 ° C for 2 hours. The mixture was concentrated in vacuo and purified by preparative HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H 2 O; modifier: 0.1% TFA) to give 2,8-dimethyl-6-(8-methyl-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)imidazo[1,2-b]pyridazine trifluoroacetate (29.7 mg, yield 39.6%) as a white solid. MS: m / z 361.3 [M+H] + .RT:0.72min (Method 3)

[0872] Example 37 - Compound 556

[0873]

[0874] Step a: To a solution of 5-bromo-3-chloropyridin-2-amine (250 mg, 1.21 mmol) and (2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)boronic acid (329.1 mg, 1.21 mmol) in dioxane (4.6 mL) and water (1.6 mL) was added Cs 2 CO 3 (1.18 g, 3.62 mmol) and Pd(dppf)Cl 2 (98.4 mg, 120.5 μmol). The mixture was stirred at 90°C for 16 hours under nitrogen. The mixture was extracted with EtOAc (15 mL x 3) and washed with Na 2 SO 4 The residue was purified by flash silica gel chromatography (0% to 20% MeOH: DCM) to give 3-chloro-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyridin-2-amine (283.6 mg, 1.04 mmol, 86% yield) as a yellow solid. MS: m / z 274.1 [M+H] + .

[0875] Step b: To a solution of tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (44.8 mg, 146.1 μmol) in t-BuOH (2 mL) was added 3-chloro-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)pyridin-2-amine (40 mg, 146.1 μmol) and NaHCO 3 (36.8 mg, 438.4 μmol), and the mixture was stirred at 80 ° C for 16 hours. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in 4M HCl in dioxane (0.37 mL) and DCM (2 mL). The mixture was stirred at 25 ° C for 2 hours. The mixture was concentrated in vacuo and purified by preparative HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H 2 O; modifier: 0.1% TFA) to give 6-(8-chloro-2-(piperidin-4-yl)imidazo[1,2-a]pyridin-6-yl)-2,8-dimethylimidazo[1,2-b]pyridazine trifluoroacetate (2.2 mg, yield 3.0%) as a white solid. MS: m / z 381.2 [M+H] + RT: 0.81min (Method 3)

[0876] Example 38 - Compound 535

[0877]

[0878] Step a: A mixture of 2-amino-4-bromo-6-chloro-phenol (500 mg, 2.25 mmol) and 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid (515.3 mg, 2.3 mmol) in PPA (5 mL) was stirred at 160 ° C for 14 hours. The mixture was poured into cold water, the mixture was neutralized with sodium bicarbonate, and the pH was adjusted to about 8 by gradually adding TEA (22.7 mg, 224.8 umol, 31.33 μL), and then tert-butyloxycarbonyl tert-butyl carbonate (490.5 mg, 2.3 mmol, 516.3 μL) was added to the mixture, and then extracted with ethyl acetate (3×10 mL). The combined organic layer was purified by Na 2 SO 4 Dry, filter and concentrate. The crude material was purified by silica gel column chromatography (PE / EtOAc=10 / 1 to 1 / 1) to give tert-butyl 4-(5-bromo-7-chloro-1,3-benzoxazol-2-yl)piperidine-1-carboxylate (400 mg, 962.2 μmol, 42.81% yield) as a brown solid. MS: m / z 415.1 [M+H] + .

[0879] Step b: To a solution of tert-butyl 4-(5-bromo-7-chloro-1,3-benzoxazol-2-yl)piperidine-1-carboxylate (90 mg, 216.5 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (60 mg, 219.7 μmol) in dioxane (4.5 mL) and water (0.5 mL) was added Pd(dppf)Cl 2 (31.7 mg, 43.3 μmol) and K 2 CO 3 (59.8 mg, 433.0 μmol), the mixture was washed with N 2 The mixture was degassed three times and stirred at 80°C for 2 hours. Then, the mixture was dissolved in MeOH and filtered, and purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 μm; mobile phase: 60% to 90% water (NH 4 HCO 3 )-CAN) to give tert-butyl 4-[7-chloro-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylate (30 mg, 62.2 μmol, yield 28.8%) as a white solid. MS: m / z 482.3 [M+H] + .

[0880] Step c: To a solution of tert-butyl 4-[7-chloro-5-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylate (30 mg, 62.2 μmol) in hexafluoroisopropanol (5 mL) was added TFA (35.5 mg, 311.2 μmol, 23.8 μL), and the mixture was stirred at 25° C. for 1 hour. Then, the mixture was dissolved in MeCN and filtered, and the product was purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 μm; mobile phase: 25% to 55% water (NH 4 HCO 3 )-CAN) to give 7-chloro-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(4-piperidinyl)-1,3-benzoxazole (8.5 mg, 22.3 μmol, yield 35.8%) as a white solid. MS: m / z 382.1 [M+H] + RT: 1.57min (Method 10)

[0881] Using the procedure described in Example 12 above, other compounds described herein are prepared by substituting appropriate starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0882]

[0883]

[0884] Example 39 - Compound 533

[0885]

[0886] Step a: At 0°C, rel-(2R,4R)-1-ethyl-N,2-dimethyl-piperidin-4-amine (41.2 mg, 263.5 μmol) and NEt 3 (48.5 mg, 479.1 μmol, 66.8 μL) was added to a mixture of 5-bromo-2-chloro-7-fluoro-1,3-benzoxazole (60 mg, 239.6 μmol) in DCM (1.5 mL), stirred at room temperature for 2 h, quenched with water, extracted with DCM (2 × 10 mL), and washed with MgSO 4 Drying, filtration and concentration afforded rel-5-bromo-N-((2S,4S)-1-ethyl-2-methylpiperidin-4-yl)-7-fluoro-N-methylbenzo[d]oxazol-2-amine which was used crude in the next step.

[0887] Step b: In N 2 rel-5-bromo-N-((2S,4S)-1-ethyl-2-methylpiperidin-4-yl)-7-fluoro-N-methylbenzo[d]oxazol-2-amine (237.7 μmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (64.9 mg, 237.7 μmol), Pd(dppf)Cl 2 A mixture of DCM (19.4 mg, 23.8 μmol), dicesium carbonate (232.3 mg, 713.0 μmol) in dioxane (1.9 mL) and water (475.3 μL) was stirred for 4 h. The residue was purified by Celite / MgSO 4(DCM / EtOAc eluent) filtered and concentrated. The mixture was purified by column chromatography (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; modifier: 0.1% TFA) to give rel-5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-N-((2S,4S)-1-ethyl-2-methylpiperidin-4-yl)-7-fluoro-N-methylbenzo[d]oxazol-2-amine (24.9 mg, 45.2 μmol, yield 19%, trifluoroacetic acid). MS: m / z 437.3 [M+H] + RT: 1.15min (Method 3)

[0888] Using the procedure described in Example 12 above, other compounds described herein are prepared by substituting appropriate starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0889]

[0890] Example 40 - Compound 468

[0891]

[0892] Step a: To a solution of 6-bromo-2-chloro-4-fluoro-1,3-benzoxazole (200 mg, 798.6 μmol) and 8-methyl-2,8-diazaspiro [4.5] decane (123.2 mg, 798.6 μmol) in dioxane (8 mL) was added TEA (242.4 mg, 2.40 mmol, 333.9 μL). The mixture was stirred at 100 ° C for 2 hours. The reactant was filtered and concentrated. The residue was purified by flash silica gel chromatography (MeOH / EtOAc=0 / 100 to 20 / 80) to give 6-bromo-4-fluoro-2-(8-methyl-2,8-diazaspiro [4.5] decane-2-yl) benzo [d] oxazole (250 mg, 678.9 μmol, 85% yield) as a yellow solid. MS: m / z 369.8 [M+H] + .

[0893] Step b: In N 2 6-Bromo-4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]dec-2-yl)benzo[d]oxazole (55.2 mg, 150 μmol), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (40.9 mg, 150 μmol), Pd(dppf)Cl 2 ·CH2 Cl 2 A mixture of 1,4-dioxane (1.9 mL) and water (475.3 μL) was stirred for 4 hours. The residue was purified by Celite / MgSO 4 (DCM / EtOAc eluent) filtered and concentrated. The mixture was purified by column chromatography (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; modifier: 0.1% TFA) to obtain 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]dec-2-yl)benzo[d]oxazole, trifluoroacetic acid (18.0 mg, 32.8 μmol, yield 27.6%, trifluoroacetic acid). MS: m / z 437.3 [M+H] + . 1 HNMR (600 MHz, DMSO-d 6 )δppm 1.72-1.78(m,1H)1.83-1.94(m,4H)2.08(t,J=7.25Hz,1H)2.43-2.47(m,3H)2.60-2.64(m,3H)2.78-2.85(m,3H)3.06-3.14(m,2H)3.40(br d,J=11.83Hz,2H)3.50(s,1H)3.68(s,1H)3.72(br t,J=7.06Hz,1H)3.76(br t,J=7.06Hz,1H)7.77-7.83(m,1H)7.88(br d,J=1.14Hz,1H)7.96-8.04(m,1H)8.15(s,1H)9.47(br s,1H).

[0894] Using the procedure described in Example 12 above, other compounds described herein are prepared by substituting appropriate starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0895]

[0896]

[0897]

[0898]

[0899] Example 41 - Compound 507

[0900]

[0901] Step a: To a solution of 6-bromo-2-chloro-4-fluoro-1,3-benzoxazole (200 mg, 798.6 μmol) and 8-methyl-2,8-diazaspiro [4.5] decane (123.2 mg, 798.6 μmol) in dioxane (8 mL) was added TEA (242.4 mg, 2.40 mmol, 333.9 μL). The mixture was stirred at 100 ° C for 2 hours. The reactant was filtered and concentrated. The residue was purified by flash silica gel chromatography (MeOH / EtOAc=0 / 100 to 20 / 80) to give 6-bromo-4-fluoro-2-(8-methyl-2,8-diazaspiro [4.5] decane-2-yl) benzo [d] oxazole (250 mg, 678.9 μmol, 85% yield) as a yellow solid. MS: m / z 369.8 [M+H] + .

[0902] Step b: To a solution of 6-bromo-4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]dec-2-yl)-1,3-benzoxazole (200 mg, 543.1 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (179.3 mg, 706.1 μmol) in dioxane (20 mL) was added KOAc (159.9 mg, 1.6 mmol) and Pd(dppf)Cl. 2 (39.7 mg, 54.3 μmol) was added to the solution. The mixture was stirred at 90°C for 2 hours under nitrogen. The crude compound was used in the next step without further purification.

[0903] Step c: 4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]dec-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (60 mg, 144.5 μmol) and 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (31.44 mg, 144.5 μmol) were added to a mixture of 4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]dec-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (60 mg, 144.5 μmol) and 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (31.44 mg, 144.5 μmol) in H 2 To a solution of 2-nitrogen (0.8 mL) and dioxane (4 mL) was added Pd(dppf)Cl 2 (10.6 mg, 14.5 μmol) and K 2 CO 3 (59.9 mg, 433.4 μmol). The mixture was stirred at 90°C for 2 hours under nitrogen. The mixture was extracted with EtOAc (25 mL x 3) and washed with Na 2 SO 4The combined organic phases were filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 μm; mobile phase: 25% to 55% water (NH 4 HCO 3 )-CAN) to give 6-(8-(difluoromethyl)-2-methylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]dec-2-yl)benzo[d]oxazole (10.6 mg, 22.5 μmol, 15.6% yield) as a white solid. MS: m / z 471.2 [M+H] + . 1 H NMR (400 MHz, methanol-d 4 )δppm=1.80-1.90(s,4H),2.05(t,J=6.7Hz,2H),2.50(s,3H),2.65(s,3H),2.86-3.05(m,4H),3.60(s,2H),3.7 9(t,J=6.9Hz,2H),7.12-7.39(m,1H),7.75(d,J=11.3Hz,1H),7.88(d,J=10.6Hz,2H),8.03(s,1H),8.54(s,1H).

[0904] Using the procedure described in Example 12 above, other compounds described herein are prepared by substituting appropriate starting materials, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0905]

[0906]

[0907] Example 42 - Compound 545

[0908]

[0909] Step a: tert-Butyl 4-(5-bromo-7-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate (75 mg, 182 mmol) was reacted with 8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (55 mg, 182 mmol) and Cs 2 CO 3 (119 mg, 365 mmol) was mixed. The solid was dissolved in dioxane (2.4 ml) and water (0.6 ml) and quenched with N 2Degas and add SPhos Pd G2 (13.1 mg, 18 mmol). Heat the reaction at 90 °C in a microwave for 1 hour. Purify the result by flash chromatography using a 0-100% EtOAc-heptane gradient to give the title compound. MS: m / z 480.2 [M+H] + ] + ; RT: 0.67min (Method 4)

[0910] Step b: To a solution of tert-butyl 4-(5-(8-fluoro-2-methylimidazo[1,2-a]pyridin-6-yl)-7-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate (161 mg, 337 mmol) in DCM was added TFA (25 uL). The reaction was heated to 45 °C for 2 hours. The reaction was quenched with sodium bicarbonate and the product was extracted with chloroform:IPA (3:1). The organic layer was concentrated in vacuo to give the title compound. MS: m / z 380.1 [M+H] + ; RT: 0.83min (method 3)

[0911] Using the procedure described in Example 17 above, other compounds described herein are prepared by substituting the appropriate boronate starting material, suitable reagents and reaction conditions in step b to obtain, for example, a compound selected from the following:

[0912]

[0913] Example 43 - Compound 548

[0914]

[0915] Step a: 6-bromo-4-methoxy-2H-benzotriazole (114.02mg, 0.5mmol, 1.0eq.) is dissolved in tetrahydrofuran (3.5mL, 0.14M), followed by the addition of tert-butyl 4-hydroxypiperidine-1-formate (100mg, 500umol, 1.0eq.), DIAD (101.11mg, 500umol, 1.0eq.) and triphenylphosphine (131315mg, 500umol, 1.0eq.). Then, the solution is stirred at RT for 16 hours, then concentrated, and then loaded onto normal phase silica in dry form for purification. Reactant is purified in 7.0 minutes by 0-100% EtOAc: heptane. Product is eluted with about 70% EtOAc. The identified eluted fractions were combined and concentrated to obtain tert-butyl 4-(6-bromo-4-methoxy-benzotriazol-2-yl)piperidine-1-carboxylate (92.3 mg, yield 23.79%). MS: m / z 357.0 [M+H-tBu] + ; RT: 1.03min (Method 4)

[0916] Step b: tert-Butyl 4-(6-bromo-4-methoxy-benzotriazol-2-yl)piperidine-1-carboxylate (46.15 mg, 112.21 umol 1.0 eq.), 8-fluoro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (30.98 mg, 112.21 umol, 1.0 eq.), cesium carbonate (73.12 mg, 224.31 umol, 2.0 eq.) and Pd(dppf)Cl2·CH2Cl2 (9.16 mg, 11.22 umol, 0.1 eq.) were dissolved in water (1 mL, 0.56 M) and dioxane (1 mL, 0.56 M), then heated to 100° C. for 16 hours. Then, the solution was concentrated to a crude product. 4-[6-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-4-methoxy-benzotriazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester was obtained as a solution (assumed yield 100%). MS: m / z 481.3 [M+H] + ; RT: 0.72min (Method 4)

[0917] Step c: 4-[6-(8-fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-4-methoxy-benzotriazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester (53.82 mg, 112 umol, 1.0 eq.) was dissolved in DCM (1 mL, 0.11 M) and then 4M HCl in dioxane (440.84 mg, 1.12 mmol, 10.0 eq.) was added. The solution was then stirred at 60°C for 16 hours, then concentrated and redissolved in a very small amount of DMSO, filtered, and purified by HPLC purification (column: XSelect CSH PrepC18 5um OBD 19×100 mm; mobile phase A: MeCN; mobile phase B: H2O, modifier: 0.1% NH4OH). 6-(8-Fluoro-2-methyl-imidazo[1,2-a]pyridin-6-yl)-4-methoxy-2-(4-piperidinyl)benzotriazole (5.2 mg, yield 12%) was obtained as a brown solid. MS: m / z 481.1 [M+H] + ; RT: 0.83min (method 3)

[0918] Example 44 - Compound 550

[0919]

[0920] Step a: To a solution of 2-amino-5-bromo-phenol (500 mg, 2.66 mmol) and 1-tert-butyloxycarbonylpiperidine-4-carboxylic acid (609.7 mg, 2.66 mmol) in DCM (10 mL) was added HATU (1.01 g, 2.66 mmol) and TEA (403.6 mg, 3.99 mmol, 556 μL). The mixture was stirred at 25 ° C for 16 hours under nitrogen. The mixture was concentrated under reduced pressure. The solution was extracted with EtOAc (20 mL×3), washed with brine, and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo.The residue was purified by silica gel chromatography (20-30% EtOAc / petroleum ether) to give the desired product tert-butyl 4-[(4-bromo-2-hydroxy-phenyl)carbamoyl]piperidine-1-carboxylate (500 mg, 1.25 mmol, 47.1% yield) as a yellow oil.

[0921] Step b: To a solution of tert-butyl 4-[(4-bromo-2-hydroxy-phenyl)carbamoyl]piperidine-1-carboxylate (2 g, 5.01 mmol) in THF (30 mL) was added triphenylphosphine (1.45 g, 5.51 mmol) and (NE)-N-isopropoxycarbonyliminocarbamic acid isopropyl ester (1.11 g, 5.51 mmol, 1.1 mL). The mixture was stirred at 25 ° C under nitrogen for 8 hours. The mixture was concentrated under reduced pressure. The solution was extracted with EtOAc (50 mL×3), washed with brine, and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo.The residue was purified by silica gel chromatography (20-30% EtOAc / petroleum ether) to give the desired product tert-butyl 4-(6-bromo-1,3-benzoxazol-2-yl)piperidine-1-carboxylate (1.6 g, 4.20 mmol, 83.8% yield) as a purple oil.

[0922] Step c: To a solution of tert-butyl 4-(6-bromo-1,3-benzoxazol-2-yl)piperidine-1-carboxylate (70 mg, 183.60 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (50.2 mg, 183.60 μmol) in dioxane (2 mL) was added Pd(dppf)Cl2 (26.9 mg, 36.72 μmol) and K 2 CO 3(50.8 mg, 367.20 μmol). Under nitrogen, the mixture was stirred at 90 ° C for 16 hours. The mixture was purified by preparative HPLC (column: Boston Green ODS 150×30 mm×5 um; conditions: water (0.05% HCl)-ACN; start B: 35; end B: 55; gradient time (min): 10; 100% B holding time (min): 2; flow rate (ml / min): 25) to give tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylate (35 mg, 78.21 μmol, yield 42.6%) as a yellow solid. MS: m / z 448.2[M+H] + .

[0923] Step d: A solution of tert-butyl 4-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylate (30 mg, 67.03 μmol) in HCl / dioxane (2 mL) was stirred at 25° C. for 16 hours under nitrogen. The mixture was purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 um; conditions: water (10 mM NH 4 HCO 3 )-ACN; start B: 12; end B: 32; gradient time (min): 10; 100% B holding time (min): 2; flow rate (ml / min): 25) to obtain 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-2-(4-piperidinyl)-1,3-benzoxazole (6 mg, 17.27 μmol, yield 25.8%) as a white solid. MS: m / z 348.2 [M+H] + . RT: 1.3 min (Method 10).

[0924] Example 45 - Compound 293

[0925]

[0926] Step a: EDCl (37.50 mg, 195.62 μmol) was added to a solution of 6-bromo-8-fluoro-imidazo[1,2-a]pyridine-2-amine (30 mg, 130.41 μmol) and 1-tert-butyloxycarbonylazetidine-3-carboxylic acid (28.87 mg, 143.46 μmol) in pyridine (2 mL). The reaction was stirred at 90 ° C for 2 hours. The mixture was filtered and concentrated. The residue was mixed with MeOH (5 mL) and H 2O (15 mL) at 20 ° C for 15 minutes. The mixture was filtered to give tert-butyl 3-[(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)carbamoyl]azetidine-1-carboxylate (30 mg, 68.21 μmol, yield 52.30%) as a brown solid. MS: m / z 413.1 [M+H] + .

[0927] Step b: To a solution of tert-butyl 3-[(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)carbamoyl]azetidine-1-carboxylate (76 mg, 183.91 μmol) in dioxane (5 mL) was added KOAc (54.15 mg, 551.74 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (46.70 mg, 183.91 μmol) and Pd(dppf)Cl 2 (20.19 mg, 27.59 μmol). 2 The mixture was stirred at 90°C for 16 hours. The mixture was quenched with water (30.0 mL) and extracted with EtOAc (20.0 mL×3). The combined organic layers were washed with brine (20.0 mL) and purified by Na 2 SO 4 The crude product was dried, filtered and concentrated under vacuum (cold) to give a crude product. The crude product was purified by silica gel chromatography (PE / EA=1 / 1=1 / 0 to 10 / 1) to give tert-butyl 3-[[8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (60 mg, 130.35 μmol, 70.9% yield) as a yellow solid.

[0928] Step c: In N 2 To a solution of tert-butyl 3-[[8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (100 mg, 217.25 μmol) in dioxane (5 mL) and water (0.5 mL) was added 6-chloro-2,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine (47.61 mg, 260.70 μmol), Pd(dppf)Cl 2 (15.90 mg, 21.72 μmol) and K 2 CO 3(90.07 mg, 651.74 μmol). The reaction was stirred at 90 °C for 2 hours. Then, the mixture was concentrated and water (80 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo to give a crude product. The crude product was purified by Combi-Flash (DCM / MeOH=10 / 1) to give tert-butyl 3-[[6-(2,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (60 mg, 124.87 μmol, 57.5% yield) as a brown solid. MS: m / z 481.3[M+H] + .

[0929] Step d: To a solution of tert-butyl 3-[[6-(2,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (10 mg, 20.81 μmol) in DCM (1 mL) was added TFA (0.5 mL). The reaction was stirred at 20 ° C for 1 hour. The mixture was concentrated in vacuo to give N-[6-(2,8-dimethyl-[1,2,4]triazolo[1,5-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]azetidine-3-carboxamide (10 mg, crude) as a yellow solid. MS: m / z 381.1[M+H] + RT: 1.453min (Method 10)

[0930] Using the procedure described in Example 21 above, other compounds described herein are prepared by substituting the appropriate boronate ester, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0931]

[0932]

[0933] Example 46 - Compound 324

[0934]

[0935] Step a: In N 2To a solution of 6-bromo-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (300 mg, 1.30 mmol) in dioxane (10 mL) and water (1 mL) was added 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (354.69 mg, 1.30 mmol), Pd(dppf)Cl 2 (95.02 mg, 129.86 μmol) and K 2 CO 3 (538.42 mg, 3.90 mmol). The reaction was stirred at 90°C for 2 hours. The mixture was concentrated and then water (80 mL) was added. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo. The residue was washed with water (30 mL) and evacuated under vacuum to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (300 mg, 1.01 mmol, 77.71% yield) as a brown solid.

[0936] Step b: To a mixture of 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (50 mg, 168.19 μmol) and 1-tert-butyloxycarbonylazetidine-3-carboxylic acid (33.84 mg, 168.19 μmol) in pyridine (3 mL) was added T 3 P (3 mL), stirred at 25 ° C for 2 hours. The reaction mixture was quenched with water (50 mL). The aqueous layer was separated and extracted with EtOAc (20 mL × 3). The combined organic layer was washed with Na 2 SO 4 Dry, filter and concentrate to give a crude product. The crude product was purified by silica gel column chromatography (PE / EtOAc=5 / 1 to 2 / 1) to give tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylate (28.9 mg, 60.15 μmol, 35.76% yield) as a yellow solid. MS: m / z 481.2 [M+H] + .

[0937] Step c:At 25 ° C, 3-[[6-(2,8-dimethylimidazo [1,2-b] pyridazine-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]carbamoyl]azetidine-1-carboxylic acid tert-butyl ester (20 mg, 41.62 μmol) was added to HCl / EA (5 mL) at one time. The mixture was stirred for 16 hours. The reaction mixture was concentrated to give a crude product N-[6-(2,8-dimethylimidazo [1,2-b] pyridazine-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]azetidine-3-carboxamide (15 mg, 39.43 μmol, yield 94.74%) as a yellow solid. The crude product was used directly in the next step.

[0938] Step d: A mixture of N-[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]azetidine-3-carboxamide (10 mg, 26.29 μmol), acetone (4.58 mg, 78.87 μmol, 5.79 μL) in EtOH (5 mL). After 30 minutes, sodium triacetoxyborohydride (16.72 mg, 78.87 μmol) was added in one portion at 25°C. The reaction was stirred at 25°C for 3 hours. The mixture was concentrated and purified by preparative HPLC (column: Welch Xtimate C18 150×25 mm×5 μm; conditions: water (FA)-ACN; start B 0; end B 30; gradient time (min) 11; 100% B hold time (min) 2; flow rate (ml / min) 25) to give N-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-1-isopropyl-azetidine-3-carboxamide (2.3 mg, 5.44 μmol, yield 20.71%) as a white solid. MS: m / z 423.2 [M+H] + ; RT:1.583 (Method 10).

[0939] Using the procedure described in Example 21 above, other compounds described herein are prepared by substituting the appropriate boronate ester, suitable reagents and reaction conditions in step a to obtain, for example, a compound selected from the following:

[0940]

[0941]

[0942] Example 47 - Compounds 361 and 367

[0943]

[0944] Step a: 6-(5-bromo-7-fluoro-indazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (100 mg, 252.36 umol, 1.0 eq.) was dissolved in dioxane (1.51 mL, 0.14 M) with 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (75.82 mg, 277.60 umol, 1.1 eq.) and PdCl2(dppf) (15.03 mg, 25.24 umol, 0.1 eq.), Cs2CO3 (246.67 mg, 757.09 umol, 3.0 eq.). Water (0.25 mL, 0.14 M) was added and degassed with N2. The vial was sealed and heated to 90 °C in a microwave for 1 hour. The organics were then injected into silica and purified by FCC using a 0-100% EtOAc-heptane gradient. 6-[5-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-indazol-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester was obtained. MS: m / z 463.5 [M+H] + ; RT 0.74 min (Method 4).

[0945] Step b: Dissolve 6-[5-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-7-fluoro-indazol-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (85.00 mg, 183.78 umol, 1.0 eq.) in DCM (2 mL, 0.09 M). Add hydrochloric acid (67.01 mg, 1.84 mmol, 10.0 eq.) and stir at room temperature for 1 hour. Concentrate the reactants and take a portion for further use in crude form. The rest is purified by HPLC purification (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; modifier: 0.1% TFA). MS: m / z 363.3[M+H] + ; RT 1.72 min (Method 1).

[0946] Step c: 6-[2-[(1R,5S)-3-azabicyclo[3.1.0]hex-6-yl]-7-fluoro-indazole-5-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (35 mg, 96 umol) was dissolved in DCM (965 uL). Sodium cyanoborohydride (18 mg, 289.73 umol) and cyclopropanecarboxaldehyde (7 mg, 96.58 umol, 7 uL) were mixed at room temperature overnight. The resultant was diluted with water and extracted with EtOAc. Then, it was purified by preparative HPLC to give 6-[2-[(1R,5S)-3-(cyclopropylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-7-fluoro-indazol-5-yl]-2,8-dimethyl-imidazo[1,2-b]pyridazine (11.6 mg, 27.85 μmol, yield 28.84%). MS: m / z 417.3 [M+H] + ; RT 1.11min (Method 4).

[0947] Example 48 - Compound 374 and / or 375

[0948]

[0949] Step a: tert-Butyl 4-(6-bromo-4-fluoro-benzotriazole-2-yl)piperidine-1-carboxylate (362.06 mg, 734.53 umol) was dissolved in dioxane (3.67 mL), followed by the addition of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (279.79 mg, 1.10 mmol) and potassium acetate (144.17 mg, 1.47 mmol). The solution was then purged with nitrogen, followed by the addition of Pd(dppf)Cl2CH2Cl2 (29.99 mg, 36.73 umol). The solution was then stirred at 100°C for 1 hour, then concentrated in vacuo, the crude product was injected onto normal phase, and purified by 0-25% MeOH:DCM. The product was eluted in 15% methanol after 12 minutes. The identified eluted fractions were combined and concentrated to obtain tert-butyl 4-[4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzotriazol-2-yl]piperidine-1-carboxylate (430.1 mg, yield 85.28%). MS: m / z 391.2 [M+H-tBu] + ; RT 1.15 min (Method 4).

[0950] Step b: tert-Butyl 4-[4-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzotriazol-2-yl]piperidine-1-carboxylate (390.26 mg, 874.39 umol), 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (313.22 mg, 1.05 mmol, hydrobromide) and cesium carbonate (1.14 g, 3.50 mmol) were dissolved in dioxane (3.28 mL) and water (1.09 mL). The solution was then purged with nitrogen followed by the addition of Pd(dppf)Cl2 CH2Cl2 (71.41 mg, 87.44 umol). The solution was then stirred at 110 ° C for 16 hours, then concentrated, loaded onto normal phase silica in dry form, and purified by 0-25% MeOH: DCM for 12 minutes. The product was eluted at 13% MeOH. The eluted fractions after identification were collected, combined and concentrated to give 4-[6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine-6-yl]-4-fluoro-benzotriazole-2-yl]piperidine-1-carboxylic acid tert-butyl ester (214.9 mg, yield 48.03%). MS: m / z 501.2 [M+H] + ; RT 0.69 min (Method 4).

[0951] Step c: 4-[6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine-6-yl]-4-fluoro-benzotriazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester (214.9 mg, 419.94 umol) was dissolved in DCM (908.87 uL) and HCl (4M, 4.20 mmol, 1.05 mL) was added. The solution immediately smoked and became turbid, and then stirred at 40°C for 16 hours, after which a precipitate was formed. The solution was then diluted with ether and the additional amount of precipitate formed was filtered off. The precipitate was washed several times with ether and then redissolved in DMSO, water and methanol, then filtered and purified by reverse phase basic conditions HPLC (column: XSelectCSH Prep C18 5um OBD 19×100mm; mobile phase A: MeCN; mobile phase B: H2O, modifier: 0.1% NH4OH). The identified eluted fractions were collected and concentrated, and then registered as is. 6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-4-fluoro-2-(4-piperidinyl)benzotriazole (99.1 mg, yield 57.62%) was obtained as a white powder. 1H NMR (400MHz, methanol-d4) δppm 2.22-2.39(m,4H)2.51-2.56(m,3H)2.82-2.92(m,2H)3.21-3.29(m,2H)5.00-5.10(m,1H) 7.15-7.42(m,1H)7.89-7.94(m,1H)8.03-8.05(m,1H)8.10-8.12(m,1H)8.43-8.45(m,1H). MS:m / z 402.2[M+H] + ; RT 0.52 min (Method 4).

[0952] Step d: 6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine-6-yl]-4-fluoro-2-(4-piperidinyl)benzotriazole (50 mg, 117.09 umol) was dissolved in acetonitrile (537.93 uL) and TEA (23.70 mg, 234.19 umol) was added. The solution was stirred for one minute and then paraformaldehyde (140.46 mg, 117.09 umol) and acetic acid (35.16 mg, 585.47 umol) were added. The solution immediately smoked and stirred at RT for 10 minutes, followed by the addition of sodium cyanoborohydride (14.72 mg, 234.19 umol). The solution was then stirred for 30 minutes, then concentrated, redissolved in DMSO and filtered, and the crude product was then injected onto a reverse phase and purified by HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H2O; modifier: 0.1% TFA) to give 6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-4-fluoro-2-(1-methyl-4-piperidinyl)benzotriazole (21.7 mg, yield 30.45%). 1HNMR (400MHz, methanol-d4) δppm 2.56-2.57(m,3H)2.59-2.65(m,2H)2.70-2.77(m,2H)2.99-3.01(m,3H)3.37-3.43(m,2H)3.58-3.64(m,1H) 3.76-3.83(m,2H)7.31-7.34(m,1H)7.98-8.02(m,1H)8.14-8.17(m,1H)8.19-8.21(m,1H)8.50-8.53(m,1H). MS:m / z 416.2[M+H] + ; RT 0.55 min (Method 4).

[0953] Using the procedure described in Example 17 above, other compounds described herein are prepared by substituting the appropriate boronate starting material, suitable reagents and reaction conditions in step b to obtain, for example, a compound selected from the following:

[0954]

[0955]

[0956] Example 48: Compound 380

[0957]

[0958] Step a: To a stirred solution of tert-butyl 4-(6-bromo-4-fluoro-benzotriazole-2-yl)piperidine-1-carboxylate (0.1 g, 250.47 umol, 1.0 eq.) in DCM (5 mL, 0.05 M) was added HCl / EtOAc (35 mg, 1 mmol, 4 eq.). The reaction mixture was stirred at RT for 1 hour. The mixture was filtered and concentrated to give a residue. The crude compound was used in the next step without further purification. 6-bromo-4-fluoro-2-(4-piperidinyl)benzotriazole (0.05 g, 59.86% yield) was obtained as a white solid. MS: m / z 299.9 [M+H] + ; RT 0.29 min (Method 9).

[0959] Step b: paraformaldehyde (260.65 mg, 217.29 umol, 1.0 eq.) and TEA (43.97 mg, 434.58 umol, 2.0 eq.) were added to a stirred solution of 6-bromo-4-fluoro-2-(4-piperidinyl)benzotriazole (0.065 g, 217.29 umol, 1.0 eq.) in 1,2-dichloroethane (1 mL, 0.2 M) and EtOH (5 mL, 0.04 M). The mixture was stirred at RT for 10 minutes. Then, sodium triacetoxyborohydride (92.10 mg, 434.58 umol, 2.0 eq.) was added. The mixture was stirred at RT for 30 minutes, then filtered and concentrated to give a residue. 6-Bromo-4-fluoro-2-(1-methyl-4-piperidinyl)benzotriazole (35 mg, 110.98 umol, yield 51.07%, purity 99.3%) was obtained as a white solid. MS: m / z 314.8 [M+H] + ; RT 0.32 min (Method 9).

[0960] Step c: To a stirred solution of 6-bromo-4-fluoro-2-(1-methyl-4-piperidinyl)benzotriazole (20 mg, 63.86 umol, 1.0 eq.) in dioxane (2.5 mL, 0.02 M) and water (0.5 mL, 0.02 M) was added cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (46.73 mg, 63.86 umol, 0.1 eq.), K2CO3 (8.83 mg, 63.86 umol, 1.0 eq.) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (17.44 mg, 63.86 umol, 1.0 eq.). The reaction mixture was stirred at 95° C. for 12 hours under N2. The mixture was filtered and concentrated to give a residue. The residue was purified by HPLC (column: XSelect CSH Prep C18 5um OBD 19×100mm; mobile phase A: MeCN; mobile phase B: H2O, modifier: 0.1% NH4OH) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-2-(1-methyl-4-piperidinyl)benzotriazole (2.8 mg, 7.34 umol, yield 11.50%, purity 99.5%) as a white solid. MS: m / z 380.0 [M+H] + ; RT 0.26 min (Method 9).

[0961] Example 49 - Compound 339

[0962]

[0963] Step a: HATU (1.14 g, 3.01 mmol) and DIPEA (972.95 mg, 7.53 mmol, 1.31 mL) were added to a stirred solution of 6-bromo-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (650 mg, 2.51 mmol) and 3-aminoazetidine-1-carboxylic acid tert-butyl ester (388.95 mg, 2.26 mmol) in DMF (10 mL). The reaction was stirred at 20 ° C for 1 hour. The residue was ground with EtOAc (20 mL) at 20 ° C for 30 minutes. 3-[(6-bromo-8-fluoro-imidazo[1,2-a]pyridine-2-carbonyl)amino]azetidine-1-carboxylic acid tert-butyl ester (400 mg, 803.41 μmol, 32.02% yield) was obtained as a yellow solid.

[0964] Step b: To tert-butyl 3-[(6-bromo-8-fluoro-imidazo[1,2-a]pyridine-2-carbonyl)amino]azetidine-1-carboxylate (150 mg, 362.98 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (99.14 mg, 362.98 μmol) in dioxane (10 mL) and H 2 To the stirred solution in O (2 mL) was added K 2 CO 3 (150.50 mg, 1.09 mmol) and Pd(dppf)Cl 2 (26.56 mg, 36.30 μmol). The reaction mixture was stirred at 90 ° C for 2 hours. The mixture was filtered and concentrated. The residue was purified by flash silica gel chromatography (DCM / MeOH = 10 / 1 to 5 / 1, TLC: DCM / MeOH = 10 / 1, Rf = 0.66) to give 3- [[6- (2,8-dimethylimidazo [1,2-b] pyridazine-6-yl) -8-fluoro-imidazo [1,2-a] pyridine-2-carbonyl] amino] azetidine -1-carboxylic acid tert-butyl ester (40 mg, 62.56 μmol, yield 17.24%, purity 75%) as a yellow solid. MS: m / z 480.2 [M + H] + ; RT: 0.357 min (Method 9).

[0965] Step c: To a solution of tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carbonyl]amino]azetidine-1-carboxylate (50 mg, 104.27 μmol) in EtOAc (2 mL) was added HCl / EtOAc (2 mL). The reaction was stirred at 20 ° C for 2 hours. The mixture was filtered and concentrated under reduced pressure to give N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxamide (40 mg, crude) as a yellow solid. MS: m / z 380.1[M+H] + ; RT: 0.243 min (Method 9).

[0966] Step d: To a solution of N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxamide (20 mg, 52.72 μmol) in DCE / EtOH (5 mL) was added cyclopropanecarboxaldehyde (5.54 mg, 79.07 μmol, 5.91 μL) and TEA (16.00 mg, 158.15 μmol, 22.04 μL). The reaction was stirred at 25 °C for 15 minutes, and then sodium triacetoxyborohydride (4.97 mg, 79.07 μmol) was added. The reaction was stirred at 25 °C for 12 hours. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (FA conditions) to give N-[1-(cyclopropylmethyl)azetidin-3-yl]-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxamide (4.49 mg, 10.03 μmol, yield 19.04%) as a white solid. MS: m / z 434.1 [M+H] + ; RT: 1.432 min (Method 10).

[0967] Using the procedure described in Example 49 above, other compounds described herein are prepared by substituting the appropriate amine in step a and / or boronate ester starting material in step b, suitable reagents and reaction conditions to obtain, for example, a compound selected from the following:

[0968]

[0969]

[0970] Example 49 - Compound 338

[0971]

[0972] Step a: To N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxamide (20 mg, 52.72 μmol), K 2 CO 31-iodo-2-methoxy-ethane (9.80 mg, 52.72 μmol) was added to a solution of (14.57 mg, 105.43 μmol) in DMF (5 mL). The reaction was stirred at 60 ° C for 12 hours. The mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC to give 6- (2,8-dimethylimidazo [1,2-b] pyridazine-6-yl) -8-fluoro-N- [1- (2-methoxyethyl) azetidin-3-yl] imidazo [1,2-a] pyridine-2-carboxamide (3.38 mg, 7.04 μmol, yield 13.3%) as a yellow solid. MS: m / z 438.2 [M + H] + ; RT: 1.43min (Method 8).

[0973] Example 50 - Compound 208

[0974]

[0975] Step a: To a solution of tert-butyl N-[3-(2-bromoacetyl)-1-bicyclo[1.1.1]pentyl]carbamate (220 mg, 723.26 umol, 1.0 eq.) and 5-bromo-3-fluoro-pyridine-2-amine (165.77 mg, 867.91 umol, 1.2 eq.) in 2-methylpropan-2-ol (5 mL, 0.14 M) was added NaHCO (121.52 mg, 1.45 mmol, 2.0 eq.). The reaction mixture was stirred at 80 ° C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (PE / EtOAc=6 / 1 to 3 / 1, TLC: PE / EtOAc=3 / 1, Rf=0.3) to give tert-butyl N-[3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-1-bicyclo[1.1.1]pentyl]carbamate (40 mg, 98.70 umol, yield 27.29%, purity 97.78%) as a white solid. MS: m / z 398.0 [M+H] + ; RT: 0.406 min (Method 9).

[0976] Step b: NaH (18.17 mg, 757.09 umol, 3.0 eq.) and MeI (70.75 mg, 504.73 umol, 2.0 eq.) were added to a solution of tert-butyl N-[3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-1-bicyclo[1.1.1]pentyl]carbamate (100 mg, 252.36 umol, 1.0 eq.) in THF (3 mL) at 0° C. The reaction was stirred at 20° C. for 3 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL×3), dried over Na2SO4, filtered and concentrated under reduced pressure to give N-[3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-1-bicyclo[1.1.1]pentyl]-N-methyl-carbamic acid tert-butyl ester (100 mg, 209.04 umol, yield 82.83%) as a yellow solid. MS: m / z 410.0 [M+H] + ; RT: 0.543 min (Method 9).

[0977] Step c: To a solution of N-[3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-1-bicyclo[1.1.1]pentyl]-N-methyl-carbamic acid tert-butyl ester (100 mg, 243.74 umol, 1.0 eq.) in EtOAc (3 mL, 0.04 M) was added HCl / EtOAC (3 mL, 0.04 M). The reaction mixture was stirred at 20 ° C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-N-methyl-bicyclo[1.1.1]pentan-1-amine (60 mg, 193.45 umol, yield 79.37%) as a yellow solid. MS: m / z 312.0[M+H] + ; RT: 0.251 min (Method 9).

[0978] Step d: To a solution of 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-N-methyl-bicyclo[1.1.1]pentan-1-amine (40 mg, 128.96 umol, 1.0 eq.) in MeOH (2 mL, 0.064 M) was added (1-ethoxycyclopropyloxy)-trimethyl-silane (33.72 mg, 193.45 umol, 1.5 eq.), TEA (13.05 mg, 128.96 umol, 1.0 eq.) and sodium cyanoborohydride (12.97 mg, 206.34 umol, 1.6 eq.) and stirred at 20° C. for 20 minutes. Then, acetic acid (23.23 mg, 386.89 umol, 3.0 eq.) was added and the mixture was stirred at 60° C. for 16 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (FA conditions) to give 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-N-cyclopropyl-N-methyl-bicyclo[1.1.1]pentan-1-amine (35 mg, 99.51 umol, yield 77.16%) as a yellow oil. MS: m / z 349.9 [M+H] + ; RT: 0.241 min (Method 9).

[0979] Step e: To a solution of 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (27.30 mg, 99.93 umol, 1.0 eq.) and 3-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-N-cyclopropyl-N-methyl-bicyclo[1.1.1]pentan-1-amine (35 mg, 99.93 umol, 1.0 eq.) in dioxane / H2O (5 mL, 0.02 M) was added cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (7.31 mg, 9.99 umol, 0.1 eq.) and K2CO3 (41.43 mg, 299.80 umol, 3.0 eq.) under N2. The reaction mixture was stirred at 90 ° C for 2 hours. The reactant was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions) to give N-cyclopropyl-3-[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-N-methyl-bicyclo[1.1.1]pentan-1-amine (13.1 mg, 30.80 umol, 30.82% yield) as a yellow solid. MS: m / z 417.2[M+H] +; RT: 1.02 min (Method 8).

[0980] Example 51 - Compound 335

[0981]

[0982] Step a: To a solution of 5-bromo-3-fluoropyridine-2-amine (25 g, 130.89 mmol, 1.0 eq.) in EtOH (300 mL, 0.44 M) was added ethyl 3-bromo-2-oxopropanoate (25.52 g, 130.89 mmol, 1.0 eq.). The mixture was stirred at 78 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was washed with saturated NaHCO (400 mL * 1) and extracted with (3 × 500 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude material was purified by silica gel column chromatography (from pure DCM to DCM / MeOH=10 / 1, TLC: PE / EA=5 / 1, Rf=0.2) to give 6-bromo-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (15 g, 52.25 mmol, yield 39.92%) as a white solid. MS: m / z 288.9 [M+H] + ; RT: 0.37 min (Method 9).

[0983] Step b: To a solution of 6-bromo-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (800 mg, 2.79 mmol, 1.0 eq.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (849.16 mg, 3.34 mmol, 1.2 eq.) in dioxane (10 mL, 0.28 M) was added KOAc (546.96 mg, 5.57 mmol, 2.0 eq.) and Pd(dppf)Cl (203.90 mg, 278.66 umol, 0.1 eq.) under N2. The reaction mixture was stirred at 90°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give (2-ethoxycarbonyl-8-fluoro-imidazo[1,2-a]pyridin-6-yl)boronic acid (600 mg, crude, 85% yield) as a black solid. MS: m / z 253.0 [M+H] + ; RT: 0.26 min (Method 9).

[0984] Step c: To a solution of (2-ethoxycarbonyl-8-fluoro-imidazo[1,2-a]pyridin-6-yl)boronic acid (600 mg, 2.38 mmol, 1.0 eq.) and 6-chloro-2,8-dimethyl-imidazo[1,2-b]pyridazine (432.42 mg, 2.38 mmol, 1.0 eq.) in dioxane (5 mL, 0.4 M) and H2O (1 mL, 0.4 M) was added K2CO3 (987.19 mg, 7.14 mmol, 3.0 eq.) and Pd(dppf)Cl2 (174.21 mg, 238.09 umol, 0.1 eq.) under N2. The reaction mixture was stirred at 90°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by flash silica gel chromatography (PE / EtOAc=10 / 1 to 5 / 1, TLC: PE / EtOAc=3 / 1, Rf=0.25) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (600 mg, 1.25 mmol, yield 52.59%) as a yellow solid. MS: m / z 354.0 [M+H] + ; RT: 0.29 min (Method 9).

[0985] Step d: To a solution of 6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (300 mg, 849.02 umol, 1.0 eq.) in MeOH (2 mL, 0.34 M) was added NaOH (101.88 mg, 2.55 mmol, 0.3 eq.) in H2O (0.5 mL, 0.34). The reaction mixture was stirred at 20 ° C for 12 hours. The reaction mixture was quenched by adding 1N HCl at 0 ° C until pH = 5 and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (270 mg, crude, 98% yield) as a yellow solid. MS: m / z 326.0 [M+H] + ; RT: 0.33 min (Method 9).

[0986] Step e: To a solution of 6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carboxylic acid (40 mg, 122.96 umol, 1.0 eq.) in pyridine (5 mL, 0.025 M) was added tert-butyl 2-(aminomethyl)piperidine-1-carboxylate (52.70 mg, 245.93 umol, 2.0 eq.) and EDCl (28.29 mg, 147.56 umol, 1.2 eq.). The reaction mixture was stirred at 80 ° C for 12 hours. The mixture was filtered and concentrated to give a residue. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (DCM / MeOH=10 / 1, TLC: DCM / MeOH=10 / 1, Rf=0.30). (2R)-2-[[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carbonyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (25 mg, 42.66 umol, yield 34.69%) was obtained as a yellow solid. MS: m / z 522.4 [M+H] + ; RT: 0.48 min (Method 9).

[0987] Step f: A solution of (2R)-2-[[[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-imidazo[1,2-a]pyridine-2-carbonyl]amino]methyl]piperidine-1-carboxylic acid tert-butyl ester (25 mg, 47.93 umol, 1.0 eq.) in HCl / EtOAc (3 mL, 0.016 M) was stirred at 25 ° C for 1 hour. The mixture was filtered and concentrated to give a residue. The crude compound was used in the next step without further purification. 6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-N-[[(2R)-2-piperidinyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide (15 mg, 34.52 umol, 72.02% yield) was obtained as a yellow solid. MS: m / z 422.2[M+H] + ; RT: 0.28 min (Method 9).

[0988] Step g: To a solution of 6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-N-[[(2R)-2-piperidinyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide (15 mg, 35.59 umol, 1.0 eq.) in DCE / EtOH (3 mL, 0.012 M) was added paraformaldehyde (64.04 mg, 53.38 umol, 1.5 eq.) and acetic acid (6.41 mg, 106.77 umol, 3.0 eq.). The reaction mixture was stirred at 25 ° C for 10 minutes, then sodium triacetoxyborohydride (11.31 mg, 53.38 umol, 1.5 eq.) was added, and the reaction mixture was stirred at 25 ° C for 12 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by preparative HPLC (NH4HCO3 conditions). 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-N-[[(2R)-1-methyl-2-piperidinyl]methyl]imidazo[1,2-a]pyridine-2-carboxamide (3.5 mg, 7.70 umol, yield 21.64%) was obtained as a yellow solid. MS: m / z 436.2 [M+H] + ; RT: 2.51 min (Method 8).

[0989]

[0990] Example 52 - Compound 540

[0991]

[0992] Step a: To a solution of tert-butyl 6-(6-bromo-8-methoxy-imidazo[1,2-a]pyridin-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (190 mg, 465.36 umol, 1.0 eq.) in dioxane (5 mL, 0.093 M) were added KOAc (137.01 mg, 1.40 mmol, 3.0 eq.), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (129.99 mg, 511.89 umol, 1.1 eq.) and cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (68.10 mg, 93.07 umol, 0.2 eq.). The mixture was stirred at 90°C under N2 for 12 hours. The crude compound was used in the next step without further purification. MS: m / z 455.9 [M+H] + ; RT: 0.56 min (Method 9).

[0993] Step b: To tert-butyl 6-[8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (100 mg, 219.61 umol, 1.0 eq.) in dioxane (5 mL, 0.037 M) and H2O (1 mL, 0.03 7M) in a solution of K2CO3 (91.05 mg, 658.83 umol, 3.0 eq.), 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (47.79 mg, 219.61 umol, 1.0 eq.) and cyclopentyl(diphenyl)phosphine; dichloropalladium; iron (32.14 mg, 43.92 umol, 0.2 eq.). Under N2, the mixture was stirred at 90°C for 2 hours. The mixture was filtered and concentrated to give a residue. The residue was purified by preparative HPLC purification (basic conditions). Compound 6-[6-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-8-methoxyimidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (19 mg, 40.04 umol, yield 18.23%). MS: m / z 511.3 [M+H] + ; RT: 0.38 min (Method 9).

[0994] Step c: To a solution of 6-[6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine-6-yl]-8-methoxy-imidazo[1,2-a]pyridin-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (12 mg, 23.50 umol, 1.0 eq.) in HCl / EtOAc (2 mL, 0.012 M). The mixture was stirred at 25 ° C for 8 hours. The mixture was filtered and concentrated to give a residue. The crude compound was used in the next step without further purification. Compound 6-[2-[(1S,5R)-3-azabicyclo[3.1.0]hex-6-yl]-8-methoxy-imidazo[1,2-a]pyridin-6-yl]-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (8 mg, 19.49 umol, yield 82.93%). MS: m / z 411.1 [M+H] + ; RT: 0.24 min (Method 9).

[0995] Step d: To a solution of 6-[2-[3-azabicyclo[3.1.0]hex-6-yl]-8-methoxy-imidazo[1,2-a]pyridin-6-yl]-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (8 mg, 19.49 umol, 1.0 eq.) in DCE / EtOH (4 mL, 0.004 M) was added paraformaldehyde (23.38 mg, 19.49 umol, 1.0 eq.). The mixture was stirred at 25 ° C for 10 minutes. Then, sodium triacetoxyborohydride (12.39 mg, 58.48 umol, 3.0 eq.) was added. The mixture was stirred at 25 ° C for 2 hours. LCMS. The mixture was filtered and concentrated to give a residue. The residue was purified by preparative HPLC purification (basic conditions). The compound 8-(difluoromethyl)-6-[8-methoxy-2-[3-methyl-3-azabicyclo[3.1.0]hexan-6-yl]imidazo[1,2-a]pyridin-6-yl]-2-methyl-imidazo[1,2-b]pyridazine (6.71 mg, 15.81 umol, yield 81.10%) was obtained as a white solid. MS: m / z 425.2 [M+H] + ; RT: 0.75 min (Method 10).

[0996] Using the procedure described in Example 52 above, other compounds described herein are prepared by substituting the appropriate boronate starting material, suitable reagents and reaction conditions in step b to obtain, for example, a compound selected from the following:

[0997]

[0998] Example 53 - Compound 290

[0999]

[1000] Step a: A mixture of tert-butyl 3-[(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)carbamoyl]azetidine-1-carboxylate (60 mg, 145.19 umol, 1.0 eq.) and TFA (1.49 g, 13.06 mmol, 90 eq.) in DCM (3 mL, 0.05 M) was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated in vacuo to give a crude product. The crude product was purified by preparative HPLC to give N-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)azetidine-3-carboxamide (30 mg, 95.81 μmol, 65.99% yield) as a yellow solid. MS: m / z 313.0[M+H] + ; RT: 1.72 min (Method 10).

[1001] Step b: Acetone (5.56 mg, 95.81 umol, 1.0 eq.) was added to a solution of N-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)azetidine-3-carboxamide (30 mg, 95.81 umol, 1.0 eq.) in EtOH (3 mL, 0.032 M), DCE (18.96 mg, 191.62 umol, 2.0 eq.) and acetic acid (17.26 mg, 287.42 umol, 3.0 eq.) and the mixture was stirred at 25 ° C for 20 minutes. Sodium triacetoxyborohydride (32.49 mg, 153.29 umol, 1.6 eq.) was added and the mixture was stirred at 25 ° C for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The crude product was purified by preparative HPLC to give N-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-1-isopropyl-azetidine-3-carboxamide (30 mg, 84.46 μmol, yield 88.15%) as a yellow solid. MS: m / z 357.0 [M+H] + ; RT: 0.94min (Method 10)

[1002] Step c: To a solution of N-(6-bromo-8-fluoro-imidazo[1,2-a]pyridin-2-yl)-1-isopropyl-azetidine-3-carboxamide (10 mg, 28.15 μmol) and [8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]boronic acid (12.78 mg, 56.31 μmol, 1.0 eq.) in dioxane (3 mL, 0.007 M) and water (1 mL, 0.007 M) was added Pd(dppf)Cl2 (2.06 mg, 2.82 μmol, 0.1 eq.) and K2CO3 (7.78 mg, 56.31 μmol, 2.0 eq.). The mixture was stirred at 90° C. for 2 hours under nitrogen. The reaction mixture was concentrated in vacuo to give a crude product. The crude product was purified by preparative HPLC (column: Boston Green ODS150*30mm*5um; conditions: water (FA)-ACN, start B 8, end B 38; gradient time (min): 14; 100% B holding time (min): 2; flow rate (ml / min): 25) to give N-[6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-1-isopropyl-azetidine-3-carboxamide (3.3 mg, 7.21 μmol, yield 25.62%) as a yellow solid. MS: m / z 458.2 [M+H] +; RT: 1.12min (Method 10)

[1003] Using the procedure described in Example 53 above, other compounds described herein are prepared by substituting the appropriate amine in step a and / or the boronate ester starting material in step c, suitable reagents and reaction conditions to obtain, for example, a compound selected from the following:

[1004]

[1005] Example 54 - Compound 411

[1006]

[1007] Step a: To a solution of 6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-4-fluoro-2-(4-piperidinyl)benzotriazole (20 mg, 49.83 μmol, 1.0 eq.) in MeCN (2 mL, 0.025 M) was added K2CO3 (13.77 mg, 99.65 μmol, 2.0 eq.) and 1-bromo-2-methoxy-ethane (6.93 mg, 49.83 μmol, 1.0 eq.). The reaction mixture was stirred at 60° C. for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (neutral conditions) to give 6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-4-fluoro-2-[1-(2-methoxyethyl)-4-piperidinyl]benzotriazole (14.9 mg, 31.61 μmol, yield 63.44%) as a yellow solid. MS: m / z 460.1 [M+H] + ; RT: 1.35min (Method 8)

[1008]

[1009] Example 55 - Compound 457

[1010]

[1011] Step a: To a solution of 6-bromo-2-chloro-4-fluoro-1,3-benzoxazole (200 mg, 798.56 μmol) and 8-methyl-2,8-diazaspiro [4.5] decane (123.18 mg, 798.56 μmol) in dioxane (8 mL) was added TEA (242.42 mg, 2.40 mmol, 333.91 μL). The mixture was stirred at 100 ° C for 2 hours. The reactant was filtered and concentrated. The residue was purified by flash silica gel chromatography (MeOH / EtOAc = 0 / 100 to 20 / 80) to give the product as a yellow solid (250 mg, 678.9 μmol, yield 85%). MS: m / z 369.8 [M + H] + .

[1012] Step b: To a solution of 6-bromo-4-fluoro-2-(8-methyl-2,8-diazaspiro[4.5]dec-2-yl)-1,3-benzoxazole (200 mg, 543.12 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (179.29 mg, 706.06 μmol) in dioxane (20 mL) was added KOAc (159.91 mg, 1.63 mmol) and Pd(dppf)Cl 2 (39.74 mg, 54.31 μmol). The mixture was stirred at 90° C. for 2 hours under nitrogen. The crude compound was used in the next step without further purification.

[1013] Step c: To a solution of 6-chloro-8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazine (30.67 mg, 140.95 μmol) and 2-(8-methyl-2,8-diazaspiro[4.5]dec-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (56 mg, 140.95 μmol) in dioxane (3 mL) and water (1 mL) was added K 2 CO 3(38.96 mg, 281.89 μmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (20.63 mg, 28.19 μmol). The mixture was stirred at 90° C. for 2 hours under nitrogen. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Boston Green ODS150*30mm*5um; conditions: water (FA)-ACN, start B16, end B 46; gradient time (min): 18; 100% B holding time (min): 2; flow rate (ml / min): 25) to give 6-[8-(difluoromethyl)-2-methyl-imidazo[1,2-b]pyridazin-6-yl]-2-(8-methyl-2,8-diazaspiro[4.5]dec-2-yl)-1,3-benzoxazole (7.6 mg, 16.80 μmol, yield 11.92%, purity 100%) as a yellow solid. MS: m / z 453.3 [M+H] + ; RT: 1.403min (Method 10)

[1014] Example 56 - Compound 531

[1015]

[1016] Step a: To a solution of 6-bromo-4-fluoro-1,3-benzoxazole-2-carboxylic acid (100 mg, 384.59 μmol) in pyridine (1 mL) was added tert-butyl 3-aminoazetidine-1-carboxylate (79.48 mg, 461.51 μmol) and EDCI (147.45 mg, 769.18 μmol). The reaction was stirred at 90 ° C for 1 hour. Then, the mixture was concentrated and water (80 mL) was added. The residue was extracted with EtOAc (50 mL×3). The combined organic layer was washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo to give a residue, which is purified by Combi-Flash (DCM / MeOH=10 / 1) to give tert-butyl 3-[(6-bromo-4-fluoro-1,3-benzoxazole-2-carbonyl)amino]azetidine-1-carboxylate (100 mg, 241.41 μmol, yield 62.77%) as a yellow solid. MS: m / z 417.0 [M+H] + .

[1017] Step b: In N 2To a solution of tert-butyl 3-[(6-bromo-4-fluoro-1,3-benzoxazole-2-carbonyl)amino]azetidine-1-carboxylate (30 mg, 72.42 μmol) in dioxane (5 mL) and water (0.5 mL) was added 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (19.78 mg, 72.42 μmol), Pd(dppf)Cl 2 (5.30 mg, 7.24 μmol) and K 2 CO 3 (30.03 mg, 217.27 μmol). The reaction was stirred at 90 °C for 2 hours. The mixture was concentrated and then water (80 mL) was added. The residue was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL) and purified by Na 2 SO 4 Dry, filter and concentrate in vacuo to give a crude product. The crude product was purified by preparative HPLC (FA) to give tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-4-fluoro-1,3-benzoxazole-2-carbonyl]amino]azetidine-1-carboxylate (20 mg, 41.62 μmol, 57.47% yield) as a brown solid. MS: m / z 481.2 [M+H] + .

[1018] Step c: To a solution of tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-4-fluoro-1,3-benzoxazole-2-carbonyl]amino]azetidine-1-carboxylate (10 mg, 20.81 μmol) in TFA (1 mL) was added DCM (2 mL). The mixture was stirred at 20 ° C for 1 hour and then concentrated in vacuo to give N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-4-fluoro-1,3-benzoxazole-2-carboxamide (10 mg, crude) as a yellow solid. MS: m / z 381.1 [M+H] + .

[1019] Step d: To a solution of N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-4-fluoro-1,3-benzoxazole-2-carboxamide (10 mg, 26.29 μmol) in EtOH (2 mL) and DCE (0.5 mL) was added TEA (5.32 mg, 52.58 μmol, 7.33 μL) and acetone (1.53 mg, 26.29 μmol, 1.93 μL). The reaction was stirred at 20 ° C for 10 minutes. Then, sodium triacetoxyborohydride (11.14 mg, 52.58 μmol) was added and the reaction was stirred at 20 ° C for another 0.5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC (FA) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-4-fluoro-N-(1-isopropylazetidin-3-yl)-1,3-benzoxazole-2-carboxamide (1 mg, 2.37 μmol, yield 9.00%) as a white solid. MS: m / z 423.2 [M+H] + ; RT: 0.92 min (Method 10).

[1020] Example 57 - Compound 245

[1021]

[1022] Step a: 5-bromo-3-fluoro-pyridine-2-amine (1 g, 5.24 mmol) and ethyl 2-bromoacetate (2.62 g, 15.71 mmol, 1.74 mL) were added to a 20 mL microwave vial. The reaction was stirred at 90 ° C for 3 hours. The resulting pink solid was filtered and added to another 20 mL microwave vial, followed by phosphorus oxychloride (16.06 g, 104.71 mmol, 9.76 mL). The mixture was stirred overnight at 90 ° C. The residue was transferred to a 500 mL round-bottom flask. Methanol was slowly added to quench POCl 3 , until no more gas is released, and the resulting suspension is concentrated, redissolved in heptane and filtered to give 6-bromo-2-chloro-8-fluoro-imidazo[1,2-a]pyridine (1.33 g, 5.34 mmol, 100% yield) as a yellow solid. MS: m / z 250.9 [M+H] + .

[1023] Step b: Pd(dppf)Cl 2(130.94 mg, 160.34 μmol) and 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (481.75 mg, 1.76 mmol) were charged into a 20 mL microwave vial, evacuated under vacuum and heated to 40 ℃ with N 2 Refill three times. 2 Under 400 mg, 1.60 mmol) of 6-bromo-2-chloro-8-fluoro-imidazo[1,2-a]pyridine in dioxane (4 mL) was stirred for 2 h. 2 The mixture was stirred at 90 ° C for 16 hours. The residue was concentrated in V10 and purified by column chromatography (EA / hexane, 0 to 100% in 20 minutes) to give 6-(2-chloro-8-fluoro-imidazo[1,2-a]pyridin-6-yl)-2,8-dimethyl-imidazo[1,2-b]pyridazine (253 mg, 801.31 μmol, 49.98% yield) as an off-white solid. MS: m / z 316.0[M+H] + .

[1024] Step c: 6-(2-chloro-8-fluoro-imidazo[1,2-a]pyridin-6-yl)-2,8-dimethyl-imidazo[1,2-b]pyridazine (25 mg, 79.18 μmol), 8-methyl-2,8-diazaspiro[4.5]decane (30.20 mg, 158.36 μmol, hydrochloride), (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (7.25 mg, 7.92 μmol) and sodium 2-methylpropan-2-ol (45.66 mg, 475.09 μmol) were added to a microwave vial, evacuated under vacuum and refilled with N2 three times, then dioxane (1 mL) was added. The reaction mixture was stirred at 90°C for 12 hours. The residue was concentrated in vacuo and purified by HPLC (column: Sunfire C18 100×19 mm, 5 mm; mobile phase A: MeCN; mobile phase B: H 2 O; modifier: 0.1% TFA) to give 2-[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-imidazo[1,2-a]pyridin-2-yl]-8-methyl-2,8-diazaspiro[4.5]decane (1.5 mg, 2.74 μmol, yield 3.46%, trifluoroacetic acid) as an orange solid. MS: m / z 434.3 [M+H] + ; RT: 0.35min (Method 4).

[1025] Example 58 - Compound 349

[1026]

[1027] Step a: To a mixture of 6-chloro-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (90 mg, 369.42 μmol, 1.0 eq.), 2,8-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-b]pyridazine (100.90 mg, 369.42 μmol, 1.0 eq.) in dioxane (10 mL, 0.037 M) was added Pd(dppf)Cl2 (27.03 mg, 36.94 μmol, 0.1 eq.), K2CO3 (153.17 mg, 1.11 mmol, 3.0 eq.) and stirred at 90° C. for 2 h under N2. The reaction mixture was then quenched with water (50 mL). The aqueous layer was separated and extracted with EtOAc (30 mL × 3). The combined organic layer was dried over Na2SO4, filtered and concentrated to give a crude product. The mixture was further purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give 6- (2,8-dimethylimidazo [1,2-b] pyridazine -6- base) -8-fluoro- [1,2,4] triazolo [1,5-a] pyridine -2- carboxylic acid ethyl ester (103 mg, 290.68 μmol, yield 78.69%) as a brown solid. MS: m / z 355.2 [M + H] + ; RT: 1.58 min (Method 10).

[1028] Step b: A mixture of 6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid ethyl ester (100 mg, 282.22 μmol, 1.0 eq.) in NaOH (56.44 mg, 1.41 mmol, 5.0 eq.) in MeOH (8 mL, 0.018 M) and H2O (8 mL, 0.018 M) was stirred at 25 ° C for 2 hours. The reaction mixture was quenched with dilute hydrochloric acid (1 mol / L, 5 ml) and water (50 mL). The aqueous layer was separated and extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product 6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (90 mg, 275.83 μmol, yield 97.74%) as a white solid. MS: m / z 327.0 [M+H] + ; RT: 1.05 min (Method 10).

[1029] Step c: Under N2, EDCl (158.63 mg, 827.50 μmol, 3.0 eq.) was added to a mixture of 6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (90 mg, 275.83 μmol, 1.0 eq.) and tert-butyl 3-aminoazetidine-1-carboxylate (47.51 mg, 275.83 μmol, 1.0 eq.) in pyridine (5 mL, 0.055 M) at once at 25 ° C. The mixture was stirred at 90 ° C for 2 hours. The mixture was cooled to 25 ° C and concentrated under reduced pressure. The residue was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (40 mL * 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Boston Green ODS150*30 mm*5 um; conditions: water (FA)-ACN; start B 20; end B 50; gradient time (min) 12; 100% B holding time (min) 2; flow rate (ml / min) 25) to give tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carbonyl]amino]azetidine-1-carboxylate (43 mg, 89.49 μmol, yield 32.44%) as a yellow solid. MS: m / z 481.2[M+H] + ; RT: 1.09 min (Method 10).

[1030] Step d: To a solution of tert-butyl 3-[[6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carbonyl]amino]azetidine-1-carboxylate (40 mg, 83.25 μmol, 1.0 eq.) in DCM (3 mL, 0.028 M) was added TFA (47.46 mg, 416.24 μmol, 5.0 eq.) in one portion at 25° C. The mixture was stirred for 16 hours. The reaction mixture was concentrated to give the crude product N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (30 mg, 78.87 μmol, yield 94.74%) as a yellow solid. The crude product was used directly in the next step. MS: m / z 381.2 [M+H] + ; RT: 0.89 min (Method 10).

[1031] Step e: To a mixture of N-(azetidin-3-yl)-6-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (30 mg, 78.87 μmol, 1.0 eq.), acetone (22.90 mg, 394.34 μmol, 5.0 eq.) in EtOH (10 mL, 0.008 M) was added TEA (39.90 mg, 394.34 μmol, 54.96 μL, 5.0 eq.). The solution was then stirred for 5 minutes before the addition of acetic acid (23.68 mg, 394.34 μmol, 5.0 eq.). After 30 minutes, sodium triacetoxyborohydride (50.15 mg, 236.61 μmol, 3.0 eq.) was added at 25 ° C. The mixture was stirred at 25 ° C. for 3 hours. The reaction mixture was purified by preparative HPLC (column: Welch Xtimate C18 150*25mm*5um; conditions: water (FA)-ACN; start B 0; end B 30; gradient time (min) 11; 100% B holding time (min) 2; flow rate (ml / min) 25) to give 6-(2,8-dimethylimidazo[1,2-b]pyridazine-6-yl)-8-fluoro-N-(1-isopropylazetidin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (17.2 mg, 40.71 μmol, yield 51.62%) as a white solid. MS: m / z 423.2[M+H] + ; RT: 1.64 min (Method 10).

[1032] Section 3. Bioassays and Data

[1033] HTT mutant and total HTRF iPSC assay protocol

[1034] The in vitro cellular assay measured mutant and total Huntingtin (HTT) protein in human induced pluripotent stem cells (iPSCs) derived from HTT patients with poly-Q49 mutations. Measurements in this assay were performed by homogeneous time-resolved fluorescence (HTRF). The mutant HTT antibody was labeled with the d-2 receptor and recognizes a region within the poly Q region. The terbium (Tb) donor antibody recognizes sequences at the N-terminus of the protein. The total HTT antibody was labeled with the d2 receptor and recognizes sequences outside the poly Q region. For each experiment, frozen iPSC aliquots were thawed from liquid nitrogen storage and cultured in flasks coated with Matrigel (Corning #354227) using complete culture medium (mTeSR TM1 Plus Basal Medium (STEMCELL Technologies Cat. No. 05825) supplemented with mTeSR TM1 Plus (STEMCELL Technologies catalog number 05852) and penicillin / streptomycin (Gibco catalog number 10378016)) and grown in the presence of 10uM Rock inhibitor (Sigma #Y0503). The flasks containing the cells were incubated overnight at 37°C and 5% CO2 (Thermo), and the next day, the medium was replaced with fresh complete medium without Rock inhibitor and incubated at 37°C and 5% CO2 for 48 hours for cell expansion. Cells were collected from the flasks using Accutase (Gibco #A1110501) and counted on a Cellometer (Nexcelom Vision). A total of 10,000 cells / well were added to a 384-well tissue culture plate (Perkin Elmer #NC1758152) pre-coated with Matrigel in a 30ul volume of complete medium containing 10uM rock inhibitor. The cell plate was centrifuged and the cells were allowed to attach overnight in a high humidity incubator (Thermo Cytomat 10) at 37°C and 5% CO2. The next day, the cells were treated with compounds. The compounds were pre-diluted in complete medium without rock inhibitors using an intermediate plate. The compounds were diluted and distributed into empty 384-well PP plates (Griener#784201) using ECHO (Labcyte#Echo555). A total of 60ul complete medium was added to each well using multidrop Combi (Thermo#5840300). Starting from 10uM, the compounds were tested in 10-point, 3-fold titrations. The culture medium in the cell plate was removed by flicking off the culture medium, and the plate was placed on a tissue and blotted dry. A 50uL volume was transferred from the compound plate to the cell assay plate using Integra (Viaflow384). The cell plate was incubated for 48 hours at 37°C, 5% CO2 and high humidity. Cell lysates were prepared by first removing the culture medium from the plate and then adding 40ul MPER lysis buffer (Thermo #78501) per well containing protease and phosphate inhibitors (Pierce #A32961). The plate was placed on an orbital shaker for 30 minutes at RT and 5ul of cell lysate was transferred to two 384-well black plates (Sigma Aldrich #CLS3821) using an Apricot Dispenser (SPT Labtech). Each plate contained 5ul of mutants per well or 5ul of total HTT HTRF assay mixture per well.The mutant HTT HTRF assay mix contained the 2B7Ab-Tb "donor" antibody (Thermo #CHDI-9000830) N-terminally labeled antibody at a final concentration of 0.4 ng per well in HTRF assay buffer (CisBio #62SDBRDF), and the MW1 (poly-Q specific)-d2 "acceptor" (Sigma #MABN2427) antibody at a final concentration of 40 ng per well in HTRF assay buffer. The total HTT HTRF assay mix contained 2B7Ab-Tb "donor" N-terminally labeled antibody at a final concentration of 0.4 ng per well in HTRF assay buffer and MAB2166-d2 (anti-huntingtin [1HU-4C8] mAb-d2 "acceptor" antibody) at a final concentration of 40 ng per well in HTRF assay buffer. All antibodies were labeled at Perkin Elmer. The assay plate was sealed and placed on an orbital shaker for one minute, then centrifuged for one minute and then incubated at room temperature for four hours. The plate was read on a PHERAstar instrument (BMG LAB TECH) and the HTRF ratio was calculated from the (337 nm / 665 nm) and (337 nm / 620 nm) outputs. IC. 50 Values ​​are derived from intact concentration-response curves plotted as percent activity versus compound concentration and fitted to a variable 4-parameter logistic model.

[1035] IC 50 The results are summarized in Table 2, where "A" represents IC 50 Values ​​less than 100 nM, "B" represents IC 50 Values ​​are between 100 nM and 1 μM, and “C” stands for IC 50 Values ​​ranged between 1 μM and 9 μM.

[1036] Table 2: mHTT protein reduction

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: is a single bond or a double bond, provided that the ring containing X1, X2, X3 and X4 is a bicyclic heteroaryl ring containing at least one N atom; X 1 is C or N; X 2 O, N or CR 2 ; X 3 is N or C; X 4 N, O, NR 4 or CR 4 ; The condition is that when X 1 When it is C, X 2 , X 3 and X 4 At least two of them are O, N or NR 4 ; R 2 and R 4 When present, each is independently selected from H, halo and C 1-6 A group consisting of alkyl groups; R 5 H, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy; R 6 This is A, -N(R 6a )-A, -C(=O)A, -N(R 6a )C(=O)-Aor-C(=O)N(R 6a )- A, and R 7 is B; in addition, when X 1 When N is 6 is B and R 7 is A; R 6a Is H or C 1-3 alkyl; A is -C 1-6 Alkylene-NR 9 R 10 , 4 to 10 membered carbocyclic group, -C 1-6 Alkylene-(4- to 10-membered carbocyclyl), Het or –C 1-6 Alkylene-Het; wherein R 9 Is H or C 1-6 alkyl; R 10 It is H, C 1-6 Alkyl, C 3-6 Cycloalkyl, –C 1-6 Alkylene-C 3-6 Cycloalkyl or –C 1-6 Alkylene-Het 1 , where Het 1 is a 4-6 membered saturated heterocyclic group; Het is a 4- to 12-membered saturated heterocyclic group, which is optionally substituted by -NR 9 R 10 or –C 1-6 Alkylene-NR 9 R 10 and optionally further substituted by 1 to 4 R 11 replace; The 4- to 10-membered carbocyclic group represented by A is optionally substituted by -NR 9 R 10 or –C 1-6 Alkylene-NR 9 R 10 and optionally substituted by 1 to 2 R 11 Replace; R 11 independently selected at each occurrence from halo, -C(=O)R 12 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 Cycloalkyl, –C 1-6 Alkylene-C 3-6 Cycloalkyl, Het 2 and –C 1-6 Alkylene-Het 2 , where Het 2 is a 4- to 6-membered saturated heterocyclic group or a 5- to 10-membered heteroaryl group, wherein said Het 2 or C 3-6 Cycloalkyl is optionally substituted by one or more independently selected from halo, C 1-6 Alkoxy and C 1-6 The alkyl group is substituted with a substituent; wherein R 12 It is H, D, halogenated, C 1-3 Alkyl, C 1-6 Alkoxy or C 3-6 Cycloalkyl; B is a 6- to 10-membered aryl, a 4- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl, the 4- to 10-membered heterocyclyl and the 5- to 10-membered heteroaryl represented by B are optionally replaced by one or more R 8 Replace; R 8 It is halogenated, -CN, -OH, C 1-6 Alkyl, C 3-6 Cycloalkyl, 5-membered or 6-membered heteroaryl, C 1-6 Haloalkyl or C 1-6 Alkoxy, or two R 8 Together with the intervening atoms, it forms a 8b substituted 4 to 7 membered heterocyclic group; wherein R 8 The 5-membered or 6-membered heteroaryl represented by 8a Substitution; wherein R 8a It is C 1-3 alkyl; and R 8b It is C 1-3 alkyl or oxo; and wherein the heterocyclyl contains 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur; and the heteroaryl contains 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

2. The compound according to claim 1, wherein the compound is represented by formula (I): or a pharmaceutically acceptable salt thereof, wherein: is a single bond or a double bond, provided that the ring containing X1, X2, X3 and X4 is a bicyclic heteroaryl ring containing at least one N atom; X 1 is C or N; X 2 O, N or CR 2 ; X 3 is N or C; X 4 Yes N, NR 4 or CR 4 ; The condition is that when X 1 When it is C, X 2 , X 3 and X 4 At least two of them are O, N or NR 4 ; R 2 and R 4 When present, each is independently selected from H, halo and C 1-6 A group consisting of alkyl groups; R 5 It is halogenated; R 6 is A, -N(R 6a )C(=O)-A or -C(=O)N(R 6a )-A, and R 7 is B; or When X 1 When N is 6 is B and R 7 is A; R 6a Is H or C 1-3 alkyl; A is -C 1-6 Alkylene-NR 9 R 10 , 4- to 10-membered saturated carbocyclic group, Het or -C 1-6 Alkylene-Het; wherein R 9 Is H or C 1-6 alkyl; R 10 It is H, C 1-6 Alkyl or -C 1-6 Alkylene-Het 1 , where Het 1 is a 4-6 membered saturated heterocyclic group; Het is a 4- to 10-membered saturated heterocyclic group, provided that when the 4- to 10-membered saturated heterocyclic group represented by Het does not contain a ring N atom, the group is replaced by -NR 9 R 10 and optionally further substituted with 1 to 2 R 11 and when the 4- to 10-membered saturated heterocyclic group represented by Het contains one or more ring N atoms, the group is optionally substituted by 1 to 3 R 11 replace; The 4- to 10-membered saturated carbocyclic group represented by A is -NR 9 R 10 and optionally substituted by 1 to 2 R 11 Replace; R 11 is independently selected at each occurrence from halo, -C(=O)R 12 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy C 1-6 Alkyl and C 3-6 Cycloalkyl; wherein R 11 The C 3-6 Cycloalkyl is optionally substituted with one or more independently selected from halo and C 1-6 The alkyl group is substituted with a substituent; wherein R 12 It is H, C 1-3 Alkyl or C 3-6 Cycloalkyl; B is a 6- to 10-membered aryl, a 4- to 10-membered heterocyclyl or a 5- to 10-membered heteroaryl, wherein the 6- to 10-membered aryl, the 4- to 10-membered heterocyclyl and the 5- to 10-membered heteroaryl represented by B are optionally replaced by one or more R 8 Replace; R 8 It is halogenated, -CN, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Alkoxy, or two R 8 Together with the intervening atoms, it forms a 8b substituted 5- to 7-membered heterocyclic group; wherein R 8 The 5-membered or 6-membered heteroaryl represented by 8a Substitution; wherein R 8a It is C 1-3 alkyl; and R 8b It is C 1-3 alkyl or oxo; and wherein the heterocyclyl contains 1-3 heteroatoms independently selected from oxygen, nitrogen and sulfur; and the heteroaryl contains 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is represented by formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX):

4. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is represented by formula (II), (III), (IV), (V), (VI), (VII) or (VIII):

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the compound is represented by formula (II):

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 5 is H, halogenated, C 1-3 Alkyl, C 1-3 Haloalkoxy or C 1-3 Alkoxy.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 5 It is F or Cl.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 5 It is H, F, Cl, -CH3, -OCHF2, -OCH3 or -OCF3.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R 5 It's F.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R 6 is A, -N(R 6a )-A、-N(R 6a )C(=O)-A or -C(=O)N(R 6a )-A;R 7 is B, and R 6a It is H or –CH3.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R 6 is A, -NHC(=O)-A or -C(=O)NH-A, and R 7 It is B.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein when X 1 When N is 6 is B, and R 7 It is A.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof; wherein X 1 is N; X 2 Yes CR 2 ; X 3 It is C; X 4 is N; R 6 is B; and R 7 It is A.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein when R 7 When it is B, R 6 It is A.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein when X 1 When N is 6 Yes-N(R 6a )-A、-N(R 6a )C(=O)-A or -C(=O)N(R 6a )-A, and R 7 is B; and where R 6a It is H or –CH3.

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein when X 1 When N is 6 is -NHC(=O)-A or -C(=O)NH-A, and R 7 It is B.

17. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein X 1 is N; X 2 Yes CR 2 ; X 3 It is C; X 4 is N; R 6 Yes-N(R 6a )-A、-N(R 6a )C(=O)-A or -C(=O)N(R 6a )-A; R 6a is H or –CH3; and R 7 It is B.

18. The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein X 1 is N; X 2 Yes CR 2 ; X 3 It is C; X 4 is N; R 6 is -NHC(=O)-A or -C(=O)NH-A; and R 7 It is B.

19. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein A is -C 1-6 Alkylene-C 3-6 Cycloalkyl, -C 1-6 Alkylene-NR 9 R 10 or –C 1-6 Alkylene-Het; wherein A represents -C 1-6 The Het in alkylene-Het is a 4- to 6-membered monocyclic saturated heterocyclic group containing a ring N atom; and R 9 and R 10 Each independently is H or C 1-4 alkyl.

20. The compound or pharmaceutically acceptable salt thereof according to claim 19, wherein -C 1-6 Het in alkylene-Het is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl.

21. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

22. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of:

23. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein: A is a 5- to 6-membered monocyclic carbocyclyl, a 5- to 8-membered bicyclic saturated bridged carbocyclyl, or Het; The Het represented by A is a 4- to 7-membered monocyclic saturated heterocyclic group, a 6- to 8-membered bicyclic saturated bridged heterocyclic group, or a 7- to 12-membered bicyclic saturated spiro or fused heterocyclic group; provided that when the Het represented by A does not contain a ring N atom, the Het is replaced by -NR 9 R 10 or –C 1-6 Alkylene-NR 9 R 10 and optionally further 1 to 2 R 11 and when the Het represented by A contains one or more ring N atoms, the Het is optionally substituted by 1 to 2 R 11 replace; and The 5- to 8-membered bicyclic saturated bridged carbocyclic group represented by A is -NR 9 R 10 , a 4- to 6-membered monocyclic saturated heterocyclic group or -C 1-6 Alkylene-NR 9 R 10 and optionally further 1 to 2 R 11 replace; R 9 and R 10 Each independently is H or C 1-4 alkyl.

24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein: A is a 5- to 6-membered monocyclic saturated carbocyclyl, a 5- to 8-membered bicyclic saturated bridged carbocyclyl or Het; The Het represented by A is a 4- to 6-membered monocyclic saturated heterocyclic group, a 6- to 8-membered bicyclic saturated bridged heterocyclic group, or a 7- to 10-membered bicyclic saturated spiro or fused heterocyclic group; provided that when the Het represented by A does not contain a ring N atom, the Het is replaced by -NR 9 R 10 and optionally further 1 to 2 R 11 and when the Het represented by A contains one or more ring N atoms, the Het is optionally substituted by 1 to 2 R 11 replace; and The 5- to 8-membered bicyclic saturated bridged carbocyclic group represented by A is -NR 9 R 10 and optionally further 1 to 2 R 11 replace; R 9 and R 10 Each independently is H or C 1-4 alkyl.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein A is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 2-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.1.1]heptyl, 2-azabicyclo[3.1.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 1-azaspiro[3.3]heptyl, 2-azaspiro[4.5]decyl, 4-azaspiro[2.5]octyl, 1-Azaspiro[4.5]decyl, 8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.2.1]octyl, 9-diazaspiro[5.5]undecyl, 2-azabicyclo[4.1.0]heptyl, 3-azabicyclo[4.1.0]heptyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.3]hexyl, 4-azaspiro[2.4]heptyl, 6-azaspiro[3.4]octyl, 2-azaspiro[4.4 ]nonyl, 2-azaspiro[3.5]nonyl, 2-azaspiro[3.4]octyl, 1-oxa-9-azaspiro[5.5]undecyl, 3-azabicyclo[3.1.0]hexyl, diazaspiro[4.5]decane, 7-diazaspiro[3.5]nonyl, diazaspiro[4.5]decyl, 7-diazaspiro[4.4]nonyl, 1-azabicyclo[3.2.1]octyl, diazaspiro[5.5]undecyl, azepanyl, 7 -azaspiro[3.5]nonyl, 5-oxa-2-azaspiro[3.4]octyl, diazabicyclo[3.2.0]heptyl, 3-azabicyclo[3.2.0]heptyl, octahydro-cyclopenta[c]pyrrolyl, hexahydro-1H-pyrrolo[3,4-c]pyrrolyl, octahydro-indolizinyl, 8-diazabicyclo[4.2.0]octyl, octahydro-isoindolyl or 1,8-diazaspiro[4.5]decane, each of which is optionally substituted by one or two R 11 replace.

26. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein A is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 2-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.1.1]heptyl, 2-azabicyclo[3.1.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 1-azaspiro[3.3]heptyl, 2-azaspiro[4.5]decyl, 4-azaspiro[2.5]octyl, 8-azaspiro[4.5]decyl, 8-azabicyclo[3.2.1]octyl, or 7-azaspiro[3.5]nonyl, each of which is optionally substituted by one or two R 11 replace.

27. The compound of claim 23 or 25, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of: Each of which is optionally replaced by one or two R 11 replace.

28. The compound of claim 24 or 26, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of: Each of which is optionally replaced by one or two R 11 replace.

29. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein A is cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, tetrahydro-2H-pyranyl, 3-oxetanyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[3.2.0]heptyl, -CH2-cyclobutyl, bicyclo[2.2.2]octyl, spiro[5.3]nonyl, or 2-oxobicyclo[2.1.1]hexyl, each of which is replaced by -NR 9 R 10 and optionally further 1 to 2 R 11 replace.

30. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein A is cyclopentyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.2]octyl, or 2-oxobicyclo[2.1.1]hexyl, each of which is replaced by -NR 9 R 10 and optionally further 1 to 2 R 11 replace.

31. The compound of claim 23 or 29, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of: Each of which is –NR 9 R 10 and optionally further 1 to 2 R 11 replace.

32. The compound of claim 24 or 30, or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of: Each of which is –NR 9 R 10 and optionally further 1 to 2 R 11 replace.

33. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 32, wherein R 11 independently selected at each occurrence from halo, -C(=O)R 12 , C 1-6 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkylene-C 3-6 Cycloalkyl, Het 2 , -C 1-6 Alkylene-Het 2 , where Het 2 is a 4-6 membered saturated heterocyclic group or a 5- to 6-membered heteroaryl group; wherein R 11 The C 3-6 Cycloalkyl or Het 2 Optionally, one to four independently selected from halo, C 1-4 Alkoxy and C 1-4 The alkyl group is substituted with a substituent; and R 12 It is H, D, halogenated, C 1-4 Alkoxy, C 1-2 Alkyl, C 3-4 Cycloalkyl.

34. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R 11 is independently selected at each occurrence from halo, -C(=O)R 12 , C 1-4 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, C 3-6 Cycloalkyl; wherein R 11 The C 3-6 The cycloalkyl group is optionally substituted by one to three independently selected from F, Cl and C 1-4 The alkyl group is substituted with a substituent; and R 12 It is H, C 1-2 Alkyl, C 3-4 Cycloalkyl.

35. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R 11 is independently selected at each occurrence from F, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)cyclopropyl, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -CH2C(CH3)3, -CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CH2CH2OCH3, -CH2CHF2, -CH2CH2F, -CH2-cyclopropyl, -CH2-cyclobutyl, cyclopropyl, cyclobutyl and cyclopentyl, Where R 11 The cyclopropyl, cyclobutyl or cyclopentyl represented by the present invention is optionally substituted by one or two independently selected from D, F, C 1-3 Alkoxy and C 1-3 The alkyl group is substituted with a substituent.

36. A compound as described in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein R 11 is independently selected at each occurrence from F, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)cyclopropyl, -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2OCH3, -CH2CH2CH2OCH3, cyclopropyl and cyclobutyl; wherein R 11 The cyclopropyl represented by is optionally substituted by one to two independently selected from F and C 1-3 The alkyl group is substituted with a substituent.

37. A compound as described in any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R 9 Is H or C 1-3 Alkyl, and R 10 It is H, C 3-6 Cycloalkyl or C 1-3 alkyl.

38. A compound as described in any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 Each independently is H or C 1-3 alkyl.

39. A compound as described in any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R 9 is H or –CH3, and R 10 is H, cyclopropyl or –CH3.

40. A compound as described in any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 Each is independently H or -CH3.

41. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 40, wherein B is phenyl, naphthyl or 8 to 10-membered bicyclic heteroaryl; wherein the phenyl, naphthyl and 8 to 10-membered bicyclic heteroaryl represented by B are optionally substituted by one to three R 8 replace.

42. A compound as described in any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein B is optionally substituted by one to three R 8 Substituted 9- or 10-membered bicyclic heteroaryl.

43. A compound as described in any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein B is optionally substituted by one to three R 8 Substituted 9-membered bicyclic heteroaryl.

44. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of phenyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, benzotriazolyl, imidazopyrazinyl, benzoxazolyl, triazolopyridinyl, benzisothiazolyl, pyrazolopyridinyl, pyrazolopyrazinyl, pyrazolopyrimidinyl, thienopyridinyl, thienopyrimidinyl, benzothiazolyl, pyrrolopyridinyl, pyrrolopyrazinyl, benzofuranyl, benzothienyl, isoquinolinyl, pyrrolotriazinyl, thienopyridinyl, triazolopyridazinyl, benzoxadiazolyl, indolyl, indolin-2-onyl, furopyridine, benzimidazolyl, benzothiadiazole, phthalazinyl, and phthalazin-1-onyl, each of which is optionally substituted by one to three R 8 replace; or B is 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onyl, each of which is optionally substituted by C 1-3 Alkyl substitution.

45. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of phenyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, benzotriazolyl, imidazopyrazinyl, benzoxazolyl, triazolopyridinyl, benzisothiazolyl, pyrazolopyridinyl, thienopyridinyl, benzothiazolyl, pyrrolopyridinyl, pyrrolopyrazinyl, benzofuranyl, benzothienyl, thienopyridinyl, triazolopyridazinyl, benzoxadiazolyl, indolyl, indolin-2-onyl, furopyridine, benzimidazolyl, benzothiadiazole, phthalazinyl, and phthalazin-1-onyl, each of which is optionally substituted by one to three R 8 replace; or B is 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-onyl, each of which is optionally substituted by C 1-3 Alkyl substitution.

46. ​​The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein B is selected from: Each of which is optionally replaced by one to three R 8 replace; or B is 47. The compound of claim 45 or a pharmaceutically acceptable salt thereof, wherein B is selected from: Each of which is optionally replaced by one to three R 8 replace; or B is 48. A compound as described in any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R 8 Each occurrence is halogenated, -CN, -OH, C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-2 Haloalkyl or C 1-2 Alkoxy.

49. A compound as described in any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein R 8 Each occurrence is halogenated, -CN, -OH, C 1-3 Alkyl, C 1-2 Haloalkyl or C 1-2 Alkoxy.

50. The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein R 8 is independently selected at each occurrence from -F, -Cl, -Br, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CHF2, -CF3, -OH, -OCH3, -OCH2CH3 and cyclopropyl.

51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 8 is independently selected at each occurrence from -F, -Cl, -CN, -CH3, -CH2CH3, -CH(CH3)2, -CHF2, -OH, -OCH3 and -OCH2CH3.

52. A compound as described in any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein R 8a is -CH3 or -CH2CH3 at each occurrence; and R 8b In each occurrence it is –CH3 or oxo.

53. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Table 1 or a pharmaceutically acceptable salt thereof.

54. The compound of claim 1, wherein the compound is represented by the formula: or a pharmaceutically acceptable salt thereof, wherein: R 5 It is halogenated; R 6 is A, -NH-C(=O)-A, -C(=O)NH-A or -NH-A; R 7 It is B; A is a 4- to 6-membered monocyclic saturated heterocyclic group, a 6- to 10-membered bicyclic saturated fused or spiro heterocyclic group, or C 3-6 The 4- to 6-membered monocyclic saturated heterocyclic group and the 6- to 10-membered bicyclic saturated fused or spiro heterocyclic group are each optionally substituted by 1 or 2 R 11 Replaced, and the C 3-6 Cycloalkyl is -NR 9 R 10 and optionally further substituted by R 11 replace; R 9 and R 10 Each independently is H or C 1-3 alkyl; Each R 11 Independently C 1-3 Alkyl or C 3-6 Cycloalkyl, B is optionally replaced by 1 to 3 R 8 substituted 9-membered bicyclic heteroaryl, wherein the 9-membered bicyclic heteroaryl has 2 to 4 N ring atoms; and Each R 8 Independently C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy.

55. The compound of claim 54 or a pharmaceutically acceptable salt thereof, wherein: R 5 It is F; A is cyclobutyl or Het, wherein Het is azetidinyl, piperidinyl, 3-azabicyclo[3.1.0]hexyl, 2,8-diazaspiro[4.5]decyl or 2,7-azaspiro[3.5]nonyl, each of which is optionally substituted by C 1-3 Alkyl or C 3-6 A is substituted with a cycloalkyl group, and the cyclobutyl group represented by A is optionally replaced by -NR 9 R 10 replace; R 9 and R 10 are each H or –CH3; and B is represented by the following formula: Each of which is optionally replaced by 1 or 2 R 8 replace; and Each R 8 Independently C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy.

56. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein A is represented by the formula: Each of which is optionally C 1-3 Alkyl substitution.

57. The compound of claim 56 or a pharmaceutically acceptable salt thereof, wherein A is represented by the formula:

58. The compound of claims 54-57 or a pharmaceutically acceptable salt thereof, wherein B is represented by the formula:

59. A compound as described in any one of claims 54-58 or a pharmaceutically acceptable salt thereof, wherein each R 8 It is –CH3, -CHF2, CF3 or OCH3.

60. A pharmaceutical composition comprising the compound according to any one of claims 1 to 59 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

61. A method of treating Huntington's disease (HD) in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-59 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 60.

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